Antibacterial agents

ABSTRACT

Hydroxyamidines and related compounds are provided which are suitable as antibacterial agents.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Ser. No. 60/175,892,filed Jan. 13, 2000, the disclosure of which is incorporated herein byreference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

[0002] Not applicable

BACKGROUND OF THE INVENTION

[0003] Resistance to currently available antibiotics has created a needfor new antibiotic agents. Infections, caused by organisms such asStaphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium andEnterococcus faecalis, have become increasingly resistant to currentlyapproved antibiotics. For example, significant clinical problems includemethicillin-resistant strains of S. aureus, which are resistant to allcurrent antibiotics except vancomycin (a drug of last resort because ofsevere side effects), and a vancomycin-resistant strain of E. faeciumenterococci which is now found world-wide. Even community-acquiredorganisms such as Streptococcus pneumoniae are increasingly resistant toantimicrobial agents, with a significant number of isolates beingresistant to penicillin and extended-spectrum cephalosporins.

[0004] The emergence and spread of resistant bacterial organisms areprimarily caused by acquisition of drug resistance genes, resulting in abroad spectrum of antibiotic resistance (e.g., extended-spectrumcephalosporin-resistant mutant .beta.-lactamases found in severalbacterial organisms). Genetic exchange of multiple-resistance genes, bytransformation, transduction and conjugation; combined with selectivepressures in settings such as hospitals where there is heavy use ofantibiotic therapies, enhance the survival and proliferation ofantimicrobial agent-resistant bacterial strains occurring by, e.g.,spontaneous mutants. Although the extent to which bacteria developresistance to antimicrobial drugs and the speed with which they do sovary with different types of drugs, resistance has inevitably developedto all antimicrobial agents (see Gold and Moellering, Jr., 1996, NewEng. J. Med., 335(19):1445-1453).

[0005] To prevent or delay the buildup of a resistant pathogenpopulation, different chemicals that are effective against a particulardisease-causing bacterium must be available. Thus, there is a need toidentify compounds which can penetrate and specifically kill thepathogenic bacterial cell, or arrest its growth without also adverselyaffecting its human, animal, or plant host.

[0006] One avenue for accomplishing this task involves the use ofcompounds targeting RNA polymerase. Accordingly, what is needed in theart are new compounds which are effective inhibitors of bacterial RNApolymerase and which are useful as antibacterial agents. The presentinvention provides such compounds along with methods for their use.

SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention provides antibacterialcompounds having the formula:

A-X-M-Y-B

[0008] or a pharmaceutically acceptable salt thereof, wherein theletters A and B each independently represent a substituted orunsubstituted aryl group or a substituted or unsubstituted heteroarylgroup. The letters X and Y each independently represent a group selectedfrom:

[0009] a bond

[0010] with the proviso that at least one of X or Y is a bond. In theabove group of radicals, the subscript m is 0, 1 or 2; the subscript nis 1 or 2; W is selected from 0, N—OR⁵, N—NR¹R², N—NR¹C(O)R⁶ andN—OC(O)R⁶; wherein R¹, R², R³, and R⁵ each independently represent H,(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl orheteroaryl(C₁-C₆)alkyl; R⁴ represents H, OH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino,(C₁-C₆)acylamino, or (C₁-C₈)heteroalkyl; and R⁶ represents H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, or (C₁-C₈)heteroalkyl. Returning to formula I, theletter M is a divalent linking group selected from:

[0011] wherein the letter U represents a group selected from:

[0012] wherein R⁷ and R⁸ are independently H, OH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino or di(C₁-C₆)alkylamino; R⁹ is H,(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl orheteroaryl(C₁-C₆)alkyl; R¹⁰ is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl orheteroaryl(C₁-C₆)alkyl; and R¹¹ and R¹² are independently H,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, C(O)R¹⁴,C(O)OR¹⁴, C(O)—NR¹⁴R¹⁵, S(O)₂R¹³ or S(O)₂NR¹⁴R¹⁵; wherein R¹³ is(C₁-C₆)alkyl, (C₁-C₆)heteroalkyl, phenyl or substituted phenyl; and R¹⁴and R¹⁵ are each independently H, (C₁-C₆)alkyl or (C₁-C₆)heteroalkyl.

[0013] In another aspect, the present invention provides pharmaceuticalcompositions comprising one or more of the above compounds in admixturewith a pharmaceutically acceptable excipient.

[0014] In yet another aspect, the present invention provides methods forcontrolling bacterial growth on a surface comprising contacting thesurface with a compound having the formula above.

[0015] In still another aspect, the present invention provides methodsfor treating or preventing bacterial growth in a subject byadministering to the subject an effective amount of a compound havingthe formula above.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Not applicable

DESCRIPTION OF THE INVENTION Definitions

[0017] The term “alkyl,” by itself or as part of another substituent,means, unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)_(m)ethyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “alkyl,” unless otherwise noted, is also meant toinclude those derivatives of alkyl defined in more detail below as“heteroalkyl,” “cycloalkyl” and “alkylene.” The term “alkylene” byitself or as part of another substituent means a divalent radicalderived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—. Typically, analkyl group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms.

[0018] The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy)are used in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Similarly, the term dialkylaminorefers to an amino group having two attached alkyl groups that can bethe same or different.

[0019] The term “heteroalkyl,” by itself or in combination with anotherterm, means, unless otherwise stated, a stable straight or branchedchain, or cyclic hydrocarbon radical, or combinations thereof,consisting of the stated number of carbon atoms and from one to threeheteroatoms selected from the group consisting of O , N, Si and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, Nand S may be placed at any interior position of the heteroalkyl group.The heteroatom Si may be placed at any position of the heteroalkylgroup, including the position at which the alkyl group is attached tothe remainder of the molecule. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Also included in the term“heteroalkyl” are those radicals described in more detail below as“heteroalkylene” and “heterocycloalkyl.” The term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—H₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini. Still further, for alkyleneand heteroalkylene linking groups, no orientation of the linking groupis implied.

[0020] The terms “cycloalkyl” and “heterocycloalkyl”, by themselves orin combination with other terms, represent, unless otherwise stated,cyclic versions of “alkyl” and “heteroalkyl”, respectively.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

[0021] The terms “halo” or “halogen,” by themselves or as part ofanother substituent, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom. Additionally, terms such as“fluoroalkyl,” are meant to include monofluoroalkyl and polyfluoroalkyl.

[0022] The term “aryl,” employed alone or in combination with otherterms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwisestated, an aromatic substituent which can be a single ring or multiplerings (up to three rings) which are fused together or linked covalently.The rings may each contain from zero to four heteroatoms selected fromN, O, and 5, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quatemized. The arylgroups that contain heteroatoms may be referred to as “heteroaryl” andcan be attached to the remainder of the molecule through a heteroatomNon-limiting examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl ring systems are selected from the group of acceptable substituentsdescribed below. The term “arylalkyl” is meant to include those radicalsin which an aryl group is attached to an alkyl group (e.g., benzyl,phenethyl, pyridylmethyl and the like) or a heteroalkyl group (e.g.,phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and thelike).

[0023] Each of the above terms (e.g., “alkyl,” “heteroalkyl” and “aryl”)are meant to include both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

[0024] Substituents for the alkyl and heteroalkyl radicals (includingthose groups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —NR′, ═O,═NR′, ═N—NR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2N+1), whereN is the total number of carbon atoms in such radical. R′, R′ and R′″each independently refer to hydrogen, unsubstituted(C₁-C₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C₁-C₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.For example, —NR′R″ is meant to include 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” in its broadest senseis meant to include groups such as haloalkyl (e.g., —CF₃ and —CH₂CF₃)and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).Preferably, the alkyl groups will have from 0-3 substituents, morepreferably 0, 1, or 2 substituents, unless otherwise specified.

[0025] Similarly, substituents for the aryl and heteroaryl groups arevaried and are selected from: -halogen, —NR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, ,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, (C₁-C₈)alkyl and heteroalkyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.

[0026] Two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -T-C(O)—(CH₂)_(q)-U-, wherein T and U are independently —NH—,—O—, —CH₂— or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)-B-, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted (C₁-C₆)alkyl.

[0027] As used herein, the term “heteroatom” is meant to include oxygen(O), nitrogen (N), sulfur (S) and silicon (Si).

[0028] The term “pharmaceutically acceptable salts” is meant to includesalts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively -nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

[0029] The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

[0030] In addition to salt forms, the present invention providescompounds which are in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that readily undergo chemicalchanges under physiological conditions to provide the compounds of thepresent invention. Additionally, prodrugs can be converted to thecompounds of the present invention by chemical or biochemical methods inan ex vivo environment. For example, prodrugs can be slowly converted tothe compounds of the present invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent.

[0031] Certain compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms are equivalent to unsolvated forms and areintended to be encompassed within the scope of the present invention.Certain compounds of the present invention may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by the present invention and areintended to be within the scope of the present invention.

[0032] Certain compounds of the present invention possess asymmetriccarbon atoms (optical centers) or double bonds; the racemates,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the present invention.

[0033] The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

DESCRIPTION OF THE EMOBODIMENTS

[0034] In one aspect, the present invention provides antibacterialcompounds having the formula:

A-X-M-Y-B  (1)

[0035] or a pharmaceutically acceptable salt thereof, wherein theletters A and B each independently represent a substituted orunsubstituted aryl group or a substituted or unsubstituted heteroarylgroup. The letters X and Y each independently represent a group selectedfrom:

[0036] a bond

[0037] with the proviso that at least one of X or Y is a bond. In theabove group of radicals, the subscript m is 0, 1 or 2; subscript n is 1or 2; W is selected from O, N—OR⁵, N—NR¹R², N—NR¹C(O)R⁶ and N—OC(O)R⁶;wherein R¹, R², R³, and R⁵ each independently represent H, (C₁-C₆)alkyl,aryl, aryl(C₁-C₆)alkyl, heteroaryl or heteroaryl(C₁-C₆)alkyl; R⁴represents H, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, (C₁-C₆)acylamino, or (C₁-C₈)heteroalkyl; and R⁶represents H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, or (C₁-C₈)heteroalkyl. Returning to formula I, theletter M is a divalent linking group selected from:

[0038] wherein the letter U represents a group selected from:

[0039] wherein R⁷ and R⁸ independently represent H, OH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino or di(C₁-C₆)alkylamino; R⁹ is H,(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl orheteroaryl(C₁-C₆)alkyl; R¹⁰ is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl orheteroaryl(C₁-C₆)alkyl; and R¹¹ and R¹² are independently H,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, C(O)R¹⁴,C(O)OR¹⁴, C(O)—NR¹⁴R¹⁵, S(O)₂R¹³ or S(O)₂NR¹⁴R¹⁵; wherein R¹³ is(C₁-C₆)alkyl, (C₁-C₆)heteroalkyl, phenyl or substituted phenyl; and R¹⁴and R¹⁵ are each independently H, (C₁-C₆)alkyl or (C₁-C₆)heteroalkyl.

[0040] Within the groups provided above, the letters X and Y willpreferably be independently selected from:

[0041] a bond

[0042] More preferably, X and Y will be selected from:

[0043] a bond

[0044] Still more preferably, X and Y are selected from:

[0045] a bond

[0046] In the most preferred embodiments, X and Y each represent a bond.

[0047] In other preferred embodiments, the letter M represents

[0048] More preferably, M represents

[0049] wherein U represents a group selected from:

[0050] Still further preferred are those embodiments in which Urepresents a group selected from

[0051] In a particularly preferred group of embodiments, the compound offormula I can be represented as formula II:

[0052] For the preferred compounds of formula (II), the letter Apreferably represents a substituted or unsubstituted phenyl, substitutedor unsubstituted naphthyl, substituted or unsubstituted quinolinyl,substituted or unsubstituted faranyl, substituted or unsubstitutedthienyl, substituted or unsubstituted indolyl, substituted orunsubstituted benzimidazolyl, substituted or unsubstituted benzofuranyl,or substituted or unsubstituted benzothienyl. More preferably, Arepresents a substituted phenyl, substituted naphthyl, substitutedquinolinyl, substituted furanyl, substituted thienyl, substitutedindolyl, substituted benzimidazolyl, substituted benzofuranyl, orsubstituted benzothienyl. Still more preferably, the letter A representsa substituted phenyl having from one to three substituents selected fromthe group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, nitro, phenyl, naphthyl, pyrrolyl, pyrazolyland —NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ are independently selected from thegroup consisting of hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl or arecombined with the nitrogen atom to which each is attached to form afour-, five-, six- or seven-membered ring optionally having additionalheteroatoms as ring members and optionally having additionalsubstituents selected from the group consisting of (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl and phenyl.

[0053] Still further preferred for compounds of formula II, are those inwhich the letter A represents a substituted phenyl group selected from:

[0054] wherein R¹⁸ represents (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy and halogen.

[0055] Returning to formula II, the letter B is preferably a phenylgroup substituted with from one to three substituents selected from thegroup consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl,(C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy halogen, phenyl and phenoxy.

[0056] In a particularly preferred group of embodiments, the compoundsare represented by formula II, wherein A is a phenyl group substitutedwith from one to three substituents selected from the group consistingof (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy,halogen and —NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ are independently selected fromthe group consisting of hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl orare combined with the nitrogen atom to which each is attached to form afour-, five-, six- or seven-membered ring optionally having additionalheteroatoms as ring members and optionally having additionalsubstituents selected from the group consisting of (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl and phenyl, and B is a phenyl group substituted withfrom one to three substituents selected from the group consisting of(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, phenyl and phenoxy.

Synthesis of Hydroxyamidine and Related Derivatives

[0057] Compounds of the present invention can be prepared using readilyavailable materials or known intermediates. The following schemesprovide a variety of synthetic avenues for the production of the subjectcompounds. One of skill in the art will understand that additionalmethods are also useful. The groups Ar and Ar′ are meant to indicate asubstituted or unsubstituted aryl group or a substituted orunsubstituted heteroaryl group. Additionally, the groups provided as R,R′ and R″ are meant to indicate, in a very general sense, an alkyl oracyl radical (including substituted and heteroatom versions thereof).Scheme I illustrates the preparation of bisarylhydroxyamidine andrelated derivatives. An oxime I can be oxidized with a variety ofhalogenating agents, such as bleach, N-chlorosuccinimide (NCS),N-bromosuccinimide (NBS), to a halo oxime ii, Treatment of ii with anucleophilic aryl amine, preferably in the presence of another tertiaryamine base, such as triethylamine, in a polar solvent, such asdimethylformamide, provides iii. Alternatively, iii can be synthesizedfrom an amide iv, Compound iv is converted to a more reactiveintermediate v upon treatment with an activating reagent, such asphosphorous pentachloride, phosphoryl trichloride, triflic anhydride, orto vi upon treatment with phosphorous pentasulfide (or Lawesson'sreagent). Reaction of the activated intermediate v or vi withhydroxyamine (or alkoxyamine) provides iii. Alternatively, reaction of vand vi with hydrazine or a substituted hydrazine leads to vii.

[0058] Scheme II outlines the preparation of various analogs bearingnonhydroxyamidine core structures. Starting from the readily accessible1,3,5-trisubstituted benzenetrifluoride compound viii, the amino groupselectively reacted with an arylisocyanate to produce the urea compoundix. The x group, which could be an amino, hydroxy, halo, or a carboxyl,was then ftinctionalized in various ways to yield more elaboratedanalogs (such as xi and xii), as depicted in the synthetic scheme.Alternatively, by starting from a different and yet readily availablestarting material, such as structure xiii, the top part of the moleculewas derivatized to introduce the desired substituents, such as an etherin structure xiv, leaving the lower half of the molecule for furtherstructural manipulation. Specifically, the nitro group in xiv wasreduced using SnCl₂ as the reducing agent or hydrogenation over Pd/C tothe corresponding aniline xv. The aniline, in turn, was transformed in avariety of means, such as through acylation and alkylation toincorporate the aminoacetamide structure bearing the desired arylgroups.

Evaluation of Compounds as Antibacterial Agents

[0059] The compounds of the present invention can be evaluated forantibacterial activity in a variety of assay formats known to those ofskill in art. The specific assays used to select the most appropriatecompound for use will typically depend on the targeted bacteria orinfection. One common assay involves evaluation of the compounds as RNApolymerase inhibitors. In this assay, buffer (250 mM KCl, 5% Glycerol,10 mM MgCl₂, 0.1 mg/ml BSA) is combined with 6 mM B-M.E., PT5 DNAtemplate, and 1.3 ug/rxn Sigma⁷⁰ saturated E. coli RNA Polymerase(Epicenter). The compound is then added in a manner not to exceed 5%DMSO. Nucleotide triphosphates are then added at the followingconcentration: 250 uM ATP, CTP and UTP with 100 uM cold CTP and 50 uMalpha ³²P CTP. The mixture is incubated for 10 min at about 37° C. A[2×] loading buffer is added and the mixture is then run on a 6% ureadenaturing PAGE until bromophenol blue reaches the edge of plate. Thegel is soaked (about 20 minutes in 10% MeOH and 10% acetic acid, toremove urea), then dried (about 55 minutes at about 85° C. (BioRad GelDrier)) and exposed to a Phospho Imaging Plate for 1 hour. The plate isthen read on a Fujix Bas1000 Imaging System and quantified using MacBasv2.0 software. An IC50 (in uM) can be calculated as the concentration ofa drug which reduces the enzyme activity to 50% of the control.

[0060] For MIC determinations for selected bacteria, log phase growingbacteria are re-suspended at 1×10⁵ bacteria per mL in LB medium. Thecompound is added and two-fold dilutions are made. The final volume inthe 96-well plate is about 100 uL. The plate is incubated at 37° C. inthe dark with shaking. After 16 hours of incubation, growth is monitoredby reading A600 or by visual inspection. MIC is defined as the minimumconcentration of drug resulting in inhibition of visible growth ofbacterial under the conditions described (above) in National Committeefor Clinical Laboratory Standards 1993. Methods for dilutionantimicrobial susceptibility tests for bacteria that grow aerobically.Approved standard M7-A3; National Committee for Clinical LaboratoryStandards: Villanova, Pa.

Formulations and Administration of Antibacterial Agents

[0061] The compounds of the present invention can be prepared andadministered in a wide variety of oral, topical and parenteral dosageforms. Thus, the compounds of the present invention can be administeredby injection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds described herein can be administered by inhalation, forexample, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. Accordingly, the presentinvention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and either a compoundof formula (I) or a pharmaceutically acceptable salt of a compound offormula (I).

[0062] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

[0063] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

[0064] The powders and tablets preferably contain from 5% or 10% to 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

[0065] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0066] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water/propylene glycol solutions. Forparenteral injection, liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0067] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizers, and thickening agents as desired. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active component in water with viscous material, such as naturalor synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

[0068] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0069] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0070] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100mg according to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

[0071] In therapeutic use for the treatment of bacterial infections, thecompounds utilized in the pharmaceutical method of the invention areadministered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. A daily dose range of about 0.1 mg/kg to about 10 mg/kg ispreferred. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of thepractitioner. Generally, treatment is initiated with smaller dosageswhich are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

[0072] The following examples are offered by way of illustration and arenot intended to limit the scope of the invention.

EXAMPLES

[0073] Reagents and solvents used below can be obtained from commercialsources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMRspectra were recorded on a Varian Gemini 400 MHz NMR spectrometer.Significant peaks are tabulated in the order: number of protons,multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br s, broad singlet) and coupling constant(s) in Hertz.Electron Ionization (EI) mass spectra were recorded on a Hewlett Packard5989A mass spectrometer. Mass spectrometry results are reported as theratio of mass over charge, followed by the relative abundance of eachion (in parentheses). In tables, a single m/e value is reported for theM+H (or as noted M−H) ion containing the most common atomic isotopes.Isotope patterns correspond to the expected formula in all cases.Electrospray ionization (ESI) mass spectrometry analysis was conductedon a Hewlett-Packard 1100 MSD electrospray mass spectrometer using theHP1 100 HPLC for sample delivery. Normally the analyte was dissolved inmethanol at 0.1 mg/mL and 1 microliter was infused with the deliverysolvent into the mass spectrometer which scanned from 100 to 1500daltons. All compounds could be analyzed in the positive ESI mode, using1:1 acetonitrile/water with 1% acetic acid as the delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery solvent.

Example 1

[0074]

Compound of Formula (Z): R′=3-CF₃, R″=H, and R′″=H

[0075] Formation of Substituted N-aryl Benzamide

[0076] To a stirred solution of aniline (5.0 g, 53.7 mmol) andtriethylamine (15 mL, 107 mmol) in CH₂Cl₂ (100 mL) at 0° C. was added asolution of 3-trifluoromethylbenzoyl chloride (9.5 g, 45.5 mmol,available from Aldrich Chemical Co.) in CH₂Cl₂ (100 mL) dropwise. After30 min. of stirring at 0° C., reaction mixture was washed with 1 N HClthree times, dried over MgSO₄, filtered and concentrated to give theamide product, which was highly pure and was used without furtherpurification.

[0077] Formation of Hydroxy Amidine

[0078] The mixture of N-phenyl 3-trifluoromethylbenzamide from above(4.0 g, 15.1 mmol) and phosphorous pentachloride (4.0 g, 1.25 equiv,18.8 mmol) in 1,2-dichloroethane (100 mL) was heated at 70° C. for 5 h.After cooling to r.t.; solvent was evaporated under redued pressure,toluene was added and the mixture was evaporated again. The residualmaterial was dissolved in acetonitrile and added to a solution ofhydroxyamine prepared by stirring hydroxyamine hydrochloride salt (2.60g, 37.5 mmol) and triethylamine (10.5 mL, 75 mmol) in acetonitrile at 0°C. for 1 h. After stirring overnight at 0° C. to r.t., the reactionmixture was diluted with ethyl acetate and washed with 0.5 N HCl andbrine. The organic layer was dried over MgSO₄, filtered, andconcentrated. The crude product was purified by flash chromatography onsilica gel eluted with 6:1 to 3:1 hexane/AcOEt to give 2.5 g of pureproduct, in 59.2% yield. ¹H (DMSO) δ 10.8 (s, 1H), 8.46 (s, 1H), 7.70(d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.55 (t, J=8.0Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 6.81 (dd, J 8.5, 7.4 Hz, 2H), 6.66 (d,J=8.5 Hz, 2H). MS (ES+): 280 [M+H]⁺.

Example 2 Compound of Formula (Z): R′=3-CF₃, R″=H, and R′″=4-Cl

[0079] The title compound was prepared in 15% yield according to methoddescribed for Example 1, and substituting 4-chloroaniline for aniline.

[0080]¹H NMR (CDCl₃) δ 8.1(s, 1H), 7.76(s, 1H), 7.63(d, J=9Hz, 1H), 7.52(d, J=9.0 Hz, 1H), 7.42 (t, J=9.0 Hz, 1H), 7.22 (s, 1H), 7.09 (d, J=8.8Hz, 2H), 6.60 (d, J=8.8 Hz, 2H). MS (ES+): 315 (M+H)⁺. Anal. Calcd. forC₁₄H₁₀ClF₃N₂O: C, 53.43; H, 3.20; N, 8.90.Found: C, 53.24; H, 3.32; N,8.72.

Example 3 Compound of Formula (Z): R′=3-CF₃, R″=H, and R′″=4-CO₂Me

[0081] The title compound was prepared in 66% yield according to methoddescribed for Example 1 except substituting 4-methoxycarbonylaniline foraniline.

[0082]¹H NMR (CD₃OD) δ 7.76 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.67 (m,2H), 7.52 (t, J=7.7 Hz, 1H), 6.69 (d, J=8.8 Hz, 2H), 3.81(s, 3H). MS(ES+): 339 (M+H)⁺.

[0083] Anal. Calcd. for C₁₆H₁₃F₃N₂O₃: C, 56.81; H, 3.87; N, 8.28. Found:C, 56.88; H, 3.96; N, 8.25.

Example 4 Compound of Formula (Z): R′=3-CF₃, R″=H, and R′″=4-OMe

[0084] The title compound was prepared in 20% yield according to methoddescribed for Example 1 except substituting 4-methoxyaniline foraniline. ¹H NMR (CDCl₃) δ 7.78 (s, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.52 (d,J=7.9 Hz, 1H), 7.36(t, J=7.9 Hz, 1H), 7.29(s, 1H), 6.66 (s, 4H), 3.70(s, 3H). MS (ES+): 311 (M+H)⁺. Anal. Calcd. for C₁₅H₁₃F₃N₂O₂: C, 58.07;H, 4.22; N, 9.03. Found: C, 58.12; H, 4.21; N, 8.92.

Example 5 Compound of Formula (Z): R′=3-Cl, R″=4-Cl, and R′″=3-Cl

[0085] The title compound was prepared in 24% yield according to methoddescribed for Example 1 except substituting 3,4-dichlorobenzoyl chloridefor 3-trifluoromethylbenzoyl chloride and substituting 3-chloroanilinefor aniline.

[0086]¹H NMR (CDCl₃) δ 7.82 (s, 1H), 7.60 (s, 1H), 7.38 (d, J=8.3 Hz,1H), 7.21 (d, J=8.4 Hz, 1H), 7.16 (s, 1H), 7.06 (t, J=8.0 Hz, 1H), 7.95(d, J=8.0 Hz, 3H), 6.77(s, 1H), 6.48(d, J=8.0 Hz, 1H). MS (ES+): 315(M+H)₊, MS (ES−): 313 (M−H)⁻.

[0087] Anal. Calcd. for C₁₃H₉C₁₃N₂O: C, 49.48; H, 2.87; N, 8.88. Found:C, 49.72; H, 2.96; N, 8.74.

Example 6 Compound of Formula (Z): R′=3-CF₃, R″=H, and R′″=3-Cl

[0088] The title compound was prepared in 69% yield according to methoddescribed for Example 1 except substituting 3-chloroaniline for aniline.

[0089]¹H NMR (CDCl₃) δ 8.85 (s, 1H), 7.77 (s, 1H), 7.65 (d, J=7.7 Hz,1H), 7.56 (d, J=7.5 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.27 (s, 1H), 7.02(t, J=8.1 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.47 (d, J=8.1Hz, 1H). MS (ES+): 315 (M+H)⁺, MS (ES−): 313 (M−H)⁻. Anal. Calcd. forC₁₄H₁₀ClF₃N₂O: C, 53.43; H, 3.20; N, 8.90.

[0090] Found: C, 53.59; H. 3.39; N, 8.67.

Example 7 Compound of Formula (Z): R′=3-SO₂CH₃, R″=H, and R′″=H

[0091] The title compound was prepared in 10% yield according to methoddescribed for Example 1 except substituting 3-methylsulfonylbenzoylchloride for 3-trifluoromethylbenzoyl chloride.

[0092]¹H NMR (CD₃OD) δ 7.92 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (d,J=7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 7.10 (t, J=7.8 Hz, 2H), 6.90 (t,1H), 6.71 (d, J=8.6 Hz, 2H), 2.95(s, 3H). MS (ES+): 291 (M+H)⁺, MS(ES−): 289 (M−H)⁻. Anal. Calcd. for C₁₄H₁₄N₂O₃S: C, 57.92; H, 4.86; N,9.65; S, 11.04. Found: C, 55.07; H, 4.79; N, 8.86; S, 9.88.

Example 8 Compound of Formula (Z): R′=3-SO₂NHPh, R″=H, and R′″=H

[0093] The title compound was prepared in 24% yield according to methoddescribed for Example 1 except substituting 3-phenylaminosulfonylbenzoylchloride for 3-trifluoromethylbenzoyl chloride.

[0094]¹H NMR (CDCl₃) δ 8.26 (s, 1H), 8.09 (s, 1H), 7.73 (d, J=7.8 Hz,1H), 7.41 (d, J=7.8 Hz, 2H), 7.27 (m, 2H), 7.12 (t, J=7.8 Hz, 2H), 6.98(t, J=9.0 Hz, 1H), 6.85 (m, 3H), 6.67 (d, J=7.5 Hz, 2H), 6.56 (d, J=7.4Hz, 2H). MS (ES+): 368 (M+H)⁺.

Example 9 Compound of Formula (Z): R′=3-Cl, R″=4-Cl, and R′″=H

[0095] The title compound was prepared in 19% yield according to methoddescribed for Example 1 except substituting 3,4-dichlorobenzoyl chloridefor 3-trifluoromethylbenzoyl chloride.

[0096]¹H NMR (CD₃OD) δ 7.54 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.25 (d,J=8.4 Hz, 1H), 7.12 (t, J=7.4 Hz, 2H), 6.91 (t, 1H), 6.71 (d, J=7.5 Hz,2H). MS (ES+): 281 (M+H)⁺. Anal. Calcd. for C₁₃H₁₀Cl₂N₂O: C, 55.54; H,3.59; N, 9.96. Found: C, 55.32; H, 3.79; N, 9.77.

Example 10 Compound of Formula (Z): R′=3-CN, R″=H, and R′″=3-Cl

[0097] The title compound was prepared in 24% yield according to methoddescribed for Example 1 except substituting 3-cyanobenzoyl chloride for3-trifluoromethylbenzoyl chloride and substituting 3-chloroaniline foraniline.

[0098]¹H NMR (DMSO) δ 11.00 (s, 1H), 8.72 (s, 1H), 7.85 (d, J=7.7 Hz,1H), 7.82 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H),7.06(t, J=8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.78(s, 1H), 6.47(d,J=7.8, 1H). MS (ES+): 272 (M+H)⁺.

Example 11 Compound of Formula (Z): R′=3-Cl, R″=H, and R′″=3-Cl

[0099] The title compound was prepared in 25% yield according to methoddescribed for Example 1 except substituting 3-chlorobenzoyl chloride for3-trifluoromethylbenzoyl chloride and substituting 3-chloroaniline foraniline.

[0100]¹H NMR(DMSO) δ 10.90 (s, 1H), 8.64 (s, 1H), 7.45 (d, J=8.6 Hz,1H), 7.44 (s, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H),7.07-(t, J=8.1 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 6.77 (s, 1H), 6.49 (d,J=8.2 Hz, 1H). MS (ES+): 281 (M+H)⁺, MS (ES−): 279 (M−H)⁻. Anal. Calcd.for C₁₃H₁₀Cl₂N₂O: C, 55.54; H, 3.59; N, 9.96.

[0101] Found: C, 55.49; H, 3.68; N, 9.81.

Example 12 Compound of Formula (Z): R′=3-CO₂CH₃, R″=H, and R′″=H

[0102] The title compound was prepared in 38% yield according to methoddescribed for Example 1 except substituting 3-methoxycarbonylbenzoylchloride for 3-trifluoromethylbenzoyl chloride.

[0103]¹H NMR (DMSO) δ 10.70 (s, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.92(d, J=7.7 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.06(t, J=8.0 Hz, 2H), 6.78 (t, J=8.0 Hz, 1H), 6.64 (d, J=7.7 Hz, 2H), 3.82(s, 3H). MS (ES+): 271 (M+H)⁺. Anal. Calcd. for C₁₅H₁₄N₂O₃: C, 66.66; H,5.22; N, 10.36. Found: C, 66.78; H, 5.34; N, 9.92.

Example 13 Compound of Formula (Z): R′=3-NO₂, R″=4-Cl, and R′″=3-Cl

[0104] Following procedures described in Example 1, substituting3-chloroaniline for aniline and substituting 4-chloro-3-nitrobenzoylchloride for 3-trifluoromethylbenzoyl chloride the title compound wasobtained in 80.0% yield. ¹H (DMSO) δ 11.2 (s, 1H), 8.78 (s, 1H), 8.09(s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.10 (t, J=7.7Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.85 (s, 1H), 6.68 (d, J=7.7 Hz, 2H).MS (ES+): 328 (M+H)⁺.

Example 14 Compound of Formula (Z): R′=3-NO₂, R″=4-pyrrolidin-1-yl, andR′″=3-Cl

[0105] The title compounds was prepared by heating a sample of thecompound (0.5 g, 1.51 mmol) from Example 13 was heated with pyrrolidine(5 equiv.) in DMSO (3 mL) at 80° C. for 4 hr followed by typical aqueouswashings and chromatographic purification.

[0106]¹H NMR (CDCl₃) δ 7.84 (d, J=2.0 Hz, 1H), 7.30 (dd, J=2.1 Hz, J=9.0Hz, 2H), 7.06 (t, J=8 Hz, 1H), (dm, J=9.0 Hz, 1H), 6.81 (t, J=2.0 Hz,1H), 6.77 (d, J=9 Hz, 1H), 6.58 (dm, J=8.1 Hz, 1H), 3.20 (m, 4H), 1.97(m, 4H). MS (ES+): 361 (M+H)⁺.

Example 15 Compound of Formula (Z): R′=3-NO₂, R″=4-Cl, and R′″=H

[0107] Following procedures described in Example 1 except substituting4-chloro-3-nitrobenzoyl chloride for 3-trifluoromethylbenzoyl chloridethe title compound was obtained in 65.8% yield.

[0108]¹H (DMSO) δ 11.0 (s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.70 (d,J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.11 (t, J=7.7 Hz, 2H), 6.84 (d,J=7.7 Hz, 1H), 6.68 (d, J=7.7 Hz, 2H). MS (ES+): 292 (M+H)⁺.

Example 16 Compound of Formula (Z): R′=3-CF₃, R″=4-F, and R′″=H

[0109] The desired compound was prepared according to the method ofExample 1 except substituting 4-fluoro-3-trifluoromethylbenzoyl chloridefor 3-trifluoromethylbenzoyl chloride (35.6% yield).

[0110]¹H (DMSO) δ 10.8 (s, 1H), 8.49 (s, 1H), 7.69 (d, J=7.5 Hz, 1H),7.65 (m, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.09 (t, J=8.0 Hz, 2H), 6.82 (t,J=8.0 Hz, 1H), 6.67(d, J=8.0 Hz, 2H). MS (ES+): 299 (M+H)⁺.

Example 17 Compound of Formula (Z): R′=3-CF₃, R″=4-F, and R′″=3-Cl

[0111] The desired compound was prepared according to the method ofExample 1 except substituting 4-fluoro-3-trifluoromethylbenzoyl chloridefor 3-trifluoromethylbenzoyl chloride and substituting 3-chloroanilinefor aniline (31.7% yield).

[0112]¹H (DMSO) δ 11.0 (s, 1H), 8.73 (s, 1H), 7.75 (d, J=6.9 Hz, 1H),7.68 (m, 1H), 7.50 (t, J=6.9 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 6.85 (d,J=8.0 Hz, 1H), 6.80(s, 1H), 6.48 (d, J=8.0 Hz, 1H). MS (ES+): 333(M+H)⁺.

Example 18 Compound of Formula (Z): R′=3-CF₃, R″=4-N₃, and R′″=3-Cl

[0113] Step 18a. Following procedures described in of Example 1 exceptsubstituting 4-fluoro-3-trifluoromethylbenzoyl chloride for3-trifluoromethylbenzoyl chloride and substituting 3-chloroaniline foraniline the corresponding N-3-chlorophenyl4-fluoro-3-trifluoromethylbenzamide was obtained.

[0114] Step 18b. A sample of the amide from above was treated in DMSOwith NaN₃ in DMSO at 110° C. for 4 hr. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate andwashed thoroughly with water and brine. The organic layer was dried overMgSO₄, filtered and concentrated to give 3-chlorophenyl4-azido-3-trifluoromethylbenzamide.

[0115] Step 18c. The mixture of N-3-chlorophenyl4-azido-3-trifluoromethylbenzamide from Step 18b (5.8 g, 17.0 mmol) andphosphorous pentachloride (4.4 g, 1.25 equiv., 21.2 mmol) in1,2-dichloroethane (100 mL) were heated at 70° C. for 5 h. After coolingto r.t., solvent was evaporated under reduced pressure. Toluene wasadded and was evaporated again. The residual material was dissolved inacetonitrile (50 mL) and was added to the solution of hydroxyamineprepared by stirring hydroxyamine hydrochloride salt (4.0 g, 57.5 mmol)and triethylamine (16 mL, 115 mmol) in acetonitrile (50 mL) at 0° C. for1 h. After stirring overnight at 0° C. to r.t., the reaction mixture wasdiluted with ethyl acetate and was washed with 0.5 N HCl and brine.Organic layer was dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by flash chromatography on silica gel elutedwith 6:1 to 3:1 hexane/AcOEt to give pure product, 4.5 g, in 70% yield.

[0116]¹H (DMSO) δ 11.1 (s, 1H), 8.69 (s, 1H), 7.71 (s, 1H), 7.68 (d,J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 6.83 (d,J=8.0 Hz, 1H), 6.81(s, 1H), 6.48 (d, J=8.0 Hz, 1H). MS (ES+): 358(M+H)⁺.

Example 19 Compound of Formula (Z): R′=3-CF₃, R″=4-NH₂, and R′″=3-Cl

[0117] To a solution of the azido-substituted compound (325 mg, 0.91mmol) from Example 18 above in EtOH-THF (6/1 mL) at 0° C. was added afreshly prepared solution of SnCl₂.2H₂O (308 mmg, 1.37 mmol, 1.5 equiv.)in 2N NaOH. TLC analysis revealed completion of reaction in 30 min. Theresulted slurry was filtered through a Celite pad, which was rinsed withethyl acetate. The filtrate was diluted with brine and ethyl acetate.The layers were separated, organic phase was washed with brine twice,dried over MgSO4, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel eluted with 3:1hexane/AcOEt to give pure product, 233 mg, in 77% yield. ¹H (DMSO) δ10.5 (s, 1H), 8.43 (s, 1H), 7.37 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.08(t, J=7.7 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.77 (s, 1H), 6.76 (d, J=7.7Hz, 1H), 6.53 (d, J=7.7 Hz, 1H), 5.8 (s, 2H). MS (ES+): 330 (M+H)⁺.

Example 20 Compound of Formula (Z): R′=3-CF₃, R″=4-NH-NH₂, and R′″=3-Cl

[0118] A sample of the 4-F compound (0.5 g, 1.51 mmol) from Example 17was heated with hydrazine monohydrate (0.75 mL) in DMSO (3 mL) at 80° C.for 4 hr. The title compound was obtained following typical aqueouswashings and chromatographic purification in 85% yield.

[0119]¹H (DMSO) δ 10.5 (s, 1H), 8.42 (s, 1H), 7.42 (s, 1H), 7.39 (d,J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.97 (s,1H), 6.78 (d, J=7.2 Hz, 1H), 6.75 (s, 1H), 6.51 (d, J=7.2 Hz, 1H), 4.25(s, 2H). MS (ES+): 345 (M+H)⁺.

Example 21 Compound of Formula (Z): R′=3-CF₃, R″=4-morpholin-1-yl, andR′″=H

[0120] A sample of the 4-F compound from Example 16 was heated withmorpholine (5 equiv.) in DMSO at 80° C. for 4 hr. The title compound wasobtained following typical aqueous washings and chromatographicpurification.

[0121]¹H NMR (DMSO): δ 10.7 (s, 1H), 8.37 (s, 1H), 7.64 (s, 1H), 7.57(d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.09 (t, J=7.3 Hz, 2H), 6.82(t, J=7.3 Hz, 1H), 6.68 (d, J=7.3 Hz, 2H), 3.69 (t, J=3.0 Hz, 4H), 2.86(t, J=3.0 Hz, 4H). MS (ES): 366 [M+H]⁺.

Example 22 Compound of Formula (Z): R′=3-CF₃, R″=4-pyrrolidin-1-yl, andR′″=H

[0122] A mixture of the 4-F compound from Example 16 (0.035 g, 0.117mmol) and pyrrolidine (0.068 ml, 0.82 mmol) in DMSO (1 ml) was heated to100° C. overnight. The mixture was poured into brine and extracted withEtOAc. The organic layer was separated, washed with brine, dried withanhydrous Na₂SO₄, concentrated by rotary evaporation and purified byflash chromatography on silica gel with a gradient elution of 30-40%EtOAc/hexanes to yield the title compound as a white solid (0.038 g,95%).

[0123]¹H NMR (DMSO-d₆): δ 10.43 (s, 1H), 8.20 (s, 1H), 7.57 (s, 1H),7.35 (d, J=9.1 Hz, 1H), 7.10 (m, 2H), 6.94 (d, J=9.1 Hz, 1H), 6.79 (m,1H), 6.70 (d, J=9.1 Hz, 2H), 3.30 (m, 4H), 1.90 (m, 4H). MS (ES): 350[M+H]⁺.

Example 23 Compound of Formula (Z): R′=3-CF₃,R″=4-(3-methyl)piperidin-1-yl, and R′″=H

[0124] The title compound was synthesized according to the proceduresused for Example 22 of above starting from the compound of Example 16(0.06 g, 0.2 mmol), 3-methylpiperidine (0.234 ml, 2 mmol) and DMSO (1ml). The reaction was conducted at 120° C. for 24 hrs. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 30-40% EtOAc/hexanes to yield the desired compound as an oil (0.029g, 38%).

[0125]¹H NMR (CDCl₃): δ 7.73 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.25 (m, 1H), 7.12 (m, 3H), 6.95 (m, 1H), 6.68 (d, J=8.4 Hz, 2H), 3.03 (m, 2H),2.59 (m, 1H), 2.29 (t, J=8.7 Hz, 1H), 1.73 (m, 5H), 0.99 (m, 1H), 0.88(d, J=6.2 Hz, 3H). MS (ES): 378 [M+H]⁺.

Example 24 Compound of Formula (Z): R′=3-CF₃,R″=4-(4-methyl)piperidin-1-yl, and R′″=H

[0126] The title compound was synthesized according to the proceduresused for Example 22 starting from a sample of compound from Example 16(0.06 g, 0.2 mmol), 4-methylpiperidine (0.236 ml, 2 mmol) and DMSO (1ml). The reaction was conducted at 120° C. for 24 hrs. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 30-40% EtOAc/hexanes to the title compound as an oil (0.027 g, 36%).

[0127]¹H NMR (CDCl₃) δ 7.73 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.25 (m,1H), 7.14 (m, 3H), 6.95 (t, J=7.7 Hz, 1H), 6.68 (d, J=8.5 Hz, 2H), 3.08(d, J=11.7 Hz, 2H), 2.66 (t, J=11.7 Hz, 2H), 1.67 (d, J=11.9 Hz, 2H),1.40 (m, 4H), 0.97 (d, J=6.2 Hz). MS (ES): 378 [M+H]⁺.

Example 25 Compound of Formula (Z): R′=3-CF₃,R″=4-(4-methyl)piperazin-1-yl, and R′″=H

[0128] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 16 (0.12 g, 0.4 mmol),1-methylpiperazine (0.311 ml, 2.8 mmol) and DMSO (1.5 ml). The reactionwas conducted at 120° C. for 2 days and then 140° C. for another 24 hrs.Purification was performed by flash chromatography on silica gel with agradient elution of 5-25% MeOH/CH₂Cl₂ to yield the title compound as awhite solid (0.138 g, 91%).

[0129]¹H NMR (DMSO) δ 10.68 (s, 1H), 8.36 (s, 1H), 7.63 (s, 1H), 7.55(d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.09 (t, J=7.9 Hz, 2H), 6.81(t, J=7.9 Hz, 1H), 6.66 (d, J=7.6 Hz, 2H), 2.86 (m, 4H), 2.43 (m, 4H),2.21 (s, 3H). MS (ES): 379 [M+H]⁺.

Example 26 Compound of Formula (Z): R′=3-CF₃,R″=4-(4-phenyl)piperazin-1-yl, and R′″=H

[0130] The title compound was synthesized according to the proceduresused for Example 22 starting from the compounds of Example 16 (0.06 g,0.2 nmmol), 1-phenylpiperazine(0.206 ml, 2 mmol) and DMSO (1 ml). Thereaction was conducted at 120° C. for 24 hrs. Purification was performedby flash chromatography on silica gel with a gradient elution of 30-40%EtOAc/hexanes to yield the title compound as a solid (0.027 g, 23%).

[0131]¹H NMR (CDCl₃) δ 7.79 (s, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.25 (m,4H), 7.15 (dd, J=7.9, 7.9 Hz, 2H), 6.97 (m, 4H), 6.89 (dd, 6.8, 6.8 Hz,1H), 6.71 (d, J=7.5 Hz, 2H), 3.31 (m, 4H), 3.11 (m, 4H). MS (ES): 441[M+H]⁺.

Example 27 Compound of Formula (Z): R′=3-CF₃, R″=4-piperidin-1-yl, andR′″=H

[0132] The title compound was synthesized according to the proceduresused for the synthesis of Example 22 starting from the compounds ofExample 16 (0.06 g, 0.2 mmol), piperidine (0.198 ml, 2 mmol) and DMSO (1ml). The reaction was conducted at 120° C. for 24 hrs. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 30-40% EtOAc/hexanes to yield the title compound as an oil (0.036 g,50%).

[0133]¹H NMR (DMSO) δ 10.66 (s, 1H), 8.34 (s, 1H), 7.62 (s, 1H), 7.54(d, J=8.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4, 8.4 Hz, 2H),6.81 (dd, J=7.5 Hz, 1H), 6.66 (d, J=7.4 Hz, 2H), 2.80 (m, 4H), 1.45-2.70(m, 6H). MS (ES): 364 [M+H]⁺.

Example 28 Compound of Formula (Z): R′=3-CF₃, R″=4-azetidinyl, and R′″=H

[0134] The title compound was synthesized according to the sameprocedure used Example 22 starting from the compounds of Example 16(0.12 g, 0.4 mmol), azetidine (0.189 ml, 2.8 mmol) and DMSO (1.5 ml).The reaction was conducted at 110° C. for 14 hrs. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 30-40% EtOAc/hexanes to yield product as a white solid (0.09 g, 67%).¹H NMR (DMSO) δ 10.39 (s, 1H), 8.18 (s, 1H), 7.48 (s, 1H), 7.34 (d,J=8.7 Hz, 1H), 7.08 (dd, J=7.7, 7.7 Hz, 2H), 6.79 (dd, J=7.5, 7.5 Hz,1H), 6.66 (d, J=8.3 Hz, 2H), 6.47 (d, J=8.7 Hz, 1H), 2.80 (m, 4H),1.45-2.70 (m, 6H). MS (ES): 336 [M+H]⁺.

Example 29 Compound of Formula (Z): R′=3-CF₃,R″=4-(S)-(2-methoxymethyl)pyrrolidin-1-yl, and R′″=H

[0135] The title compound was synthesized according to the sameprocedure for Example 22 starting from the compounds of Example 16,(S)(+)-2-methoxymethylpyrrolidine (0.346 ml, 2.8 mmol) and DMSO (1.5ml). The reaction was conducted at 120° C. for 2 days. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 30-45% EtOAc/hexanes to yield product as an oil (0.04 g, 25%).

[0136]¹H NMR (DMSO) δ 10.55 (s, 1H), 8.29 (s, 1H), 7.58 (s, 1H), 7.45(d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.08 (dd, J=7.6, 7.6 Hz, 2H),6.80 (dd, J=7.6, 7.6 Hz, 1H), 6.67 (d, J=7.6 Hz, 2H), 4.33 (t, J=5.6 Hz,1H), 3.87 (m, 1H), 3.40 (m, 1H), 3.21 (m, 1H), 3.11 (s, 3H), 2.95 (m,1H), 2.1 (m, 1H), 1.65-1.90 (m, 3H). MS (ES): 394 [M+H]⁺.

Example 30 Compound of Formula (Z): R′=3-CF₃,R″=4-[(R)-3-dimethylamino]pyrrolidin-1-yl, and R′″=H

[0137] The title compound was synthesized according to the sameprocedure used for Example 22 starting from the compounds of Example 16(0.12 g, 0.4 mmol), (R)(+)-3-dimethylaminopyrrolidine (0.355 ml, 2.8mmol) and DMSO (1.5 ml). The reaction was conducted at 120° C. for 24hrs. Purification was performed by flash chromatography on silica gelwith a gradient elution of 5-25% MeOH/CH₂Cl₂ to yield desired product asa white solid (0.105 g, 67%).

[0138]¹H NMR (DMSO) δ 10.45 (s, 1H), 8.22 (s, 1H), 7.56 (s, 1H), 7.36(d, J 11.1 Hz, 1H), 7.09 (dd, J=8.3, 8.3 Hz, 2H), 6.95 (d, J=8.3 Hz,1H), 6.80 (d, J=6.9 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 3.3-3.5 (m, 2H),3.22 (t, J=8.3 Hz, 1H), 2.71 (quint, J=7.8 Hz, 1H), 2.16 (s, 6H), 2.09(m, 1H), 1.74 (quint, J=9.4 Hz, 1H). MS (ES): 393 [M+H]⁺.

Example 31 Compound of Formula (Z): R′=3-CF₃,R″=4-[(±)-2-methyl]pyrrolidin-1-yl, and R′″=H

[0139] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 16 (0.12 g, 0.4 mmol),2-methylpyrrolidine (0.286 ml, 2.8 mmol) and DMSO (1.5 ml). The reactionwas conducted at 120° C. for 1.5 days. Purification was performed byflash chromatography on silica gel with a gradient elution of 25-35%EtOAc/hexanes to yield product as a white solid (0.09 g, 62%).

[0140]¹H NMR (DMSO) δ 10.5 (s, 1H), 8.22 (s, 1H), 7.59 (s, 1H), 7.43 (d,J=8.3 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.09 (dd, J=7.9, 7.9 Hz, 2H),6.80 (dd, J=7.8, 7.8 Hz, 1H), 6.67 (d, J=7.6 Hz, 2H), 3.72 (m, 1H), 3.46(m, 1H), 2.95 (m, 1H), 2.11 (m, 1H), 1.86 (m, 1H), 1.75 (m, 1H), 1.50(m, 1H), 0.95 (d, J=6.0 Hz, 3H). MS (ES): 364 [M+H]⁺.

Example 32 Compound of Formula (Z): R″=3-CF₃,R″=4-[(R)-3-hydroxy]pyrrolidin-1-yl, and R′″=H

[0141] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 16 (0.12 g, 0.4 mmol),(R)(+)-3-pyrrolidinol (0.233 ml, 2.8 mmol) and DMSO (1.5 ml). Thereaction was conducted at 120° C. overnight. Purification was performedby flash chromatography on silica gel with a gradient elution of 60-100%EtOAc/hexanes to give product as a white solid (0.1 g, 68%).

[0142]¹H NMR (DMSO) δ 10.41 (s, 1H), 8.20 (s, 1H), 7.56 (s, 1H), 7.34(d, J=8.9 Hz, 1H), 7.09 (dd, J=7.6, 7.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 1H),6.79 (dd, J=7.3, 7.3 Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 4.96 (d, J=3.2 Hz,1H), 4.33 (m, 1H), 3.4-3.6 (m, 2H), 3.28 (m, 1H), 3.10 (d, J=10.6, 1H),1.96 (m, 1H), 1.84 (m, 1H). MS (ES): 366 [M+H]⁺.

Example 33 Compound of Formula (Z): R′=3-CF₃,R″=4-[(S)-2-hydroxymethyl]pyrrolidin-1-yl, and R′″=H

[0143] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 16 (0.12 g, 0.4 mmol),(S)(+)-2-hydroxymethylpyrrolidine (0.276 ml, 2.8 mmol) and DMSO (1.5ml). The reaction was conducted at 120° C. overnight. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 60-100% EtOAc/hexanes to give product as a white solid (0.05 g, 33%).

[0144]¹H NMR (DMSO) δ 10.54 (s, 1H), 8.27 (s, 1H), 7.56 (s, 1H), 7.42(d, J=8.7 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.09 (dd, J=7.9, 7.9 Hz, 2H),6.81 (dd, J=7.4, 7.4 Hz, 1H), 6.67 (d, J=7.6 Hz, 2H), 4.52 (t, J=5.0 Hz,1H), 3.77 (m, 1H), 3.43 (m, 1H), 3.16 (m, 2H), 2.99 (m, 1H), 2.10 (m,1H), 1.74 (m, 3H). MS (ES): 380 [M+H]⁺.

Example 34 Compound of Formula (Z): R′=3-CF₃,R″=4-(4-pyrrolidin-1-yl)piperidin-1-yl, and R′″=H

[0145] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 16 (0.12 g, 0.4 mmol),4-(1-pyrrolidinyl)piperidine (0.432 g, 2.8 mmol) and DMSO (1.5 ml). Thereaction was conducted at 120° C. for 2.5 days. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 0-10% NH₄OH in 30% MeOH/CH₂Cl₂ to yield product as a white solid(0.105 g, 61%).

[0146]¹H NMR (DMSO) δ 10.68 (s, 1H), 8.34 (s, 1H), 7.62 (s, 1H), 7.52(d, J=8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.09 (dd, J=7.9, 7.9 Hz, 2H),6.80 (dd, J=7.7, 7.7 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 2.97 (m, 2H), 2.72(m, 2H), 2.10 (m, 1H), 1.89 (m, 4H), 1.67 (m, 6H), 1.50 (m, 2H). MS(ES): 433 [M+H]⁺.

Example 35 Compound of Formula (Z): R′=3-CF₃, R″=4-pyrrolin-1-yl, andR′″=H

[0147] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 16 (0.12 g, 0.4 mmol),pyrroline (0.215 ml, 2.8 mmol) and DMSO (1.5 ml). The reaction wasconducted at 130° C. for 1.5 days. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-45%EtOAc/hexanes to yield product as a white solid (0.062 g, 45%).

[0148]¹H NMR (DMSO) δ 10.44 (s, 1H), 8.23 (s, 1H), 7.61 (s, 1H), 7.36(d, J=8.8 Hz, 1H), 7.09 (dd, J=7.4, 7.4 Hz, 2H), 6.93 (d, J=8.8 Hz, 1H),6.80 (dd, J=7.8, 7.8 Hz, 1H), 6.68 (dd, J=8.4, 8.4 Hz, 2H), 5.97 (s,2H), 4.20 (s, 4H). MS (ES): 348 [M+H]⁺.

Example 36 Compound of Formula (Z): R′=3-CF₃, R″=4-cyclobutylamino, andR′″=H

[0149] Synthesized according to the same procedure used for Example 22starting from the compounds of Example 16 (0.12 g, 0.4 mmol),cyclobutylamine (0.239 ml, 2.8 mmol) and DMSO (1.5 ml). The reaction wasconducted at 130° C. for 24 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-40%EtOAc/hexanes to yield product as a white solid (0.1 g, 72%).

[0150]¹H NMR (DMSO) δ 10.36 (s, 1H), 8.17 (s, 1H), 7.41 (s, 1H), 7.33(d, J=8.9 Hz, 1H), 7.08 (dd, J=7.9, 7.9 Hz, 2H), 6.79 (dd, J=7.2, 7.2Hz, 1H), 6.66 (m, 3H), 5.37 (d, J=6.2 Hz, 1H), 3.91 (m, 1H), 2.32 (m,2H), 1.97 (m, 2H), 1.69 (m, 2H). MS (ES): 350 [M+H]⁺.

Example 37 Compound of Formula (Z): R′=3-CF₃, R″=4-cyclopentylamino, andR′″=3-Cl

[0151] Synthesized according to the same procedure as was used Example22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),cyclopentylamine (0.201 ml, 2.1 mmol) and DMSO (1.2 ml). The reactionwas conducted at 130° C. for 20 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to yield product as a white solid (0.08 g, 67%).

[0152]¹H NMR (DMSO) δ 10.54 (s, 1H), 8.45 (s, 1H), 7.45 (s, 1H), 7.39(d, J=8.9 Hz, 1H), 7.07 (dd, J=7.3, 7.3 Hz, 1H), 6.82 (m, 3H), 6.51 (d,J=7.3 Hz, 1H), 4.89 (d, J=5.6 Hz, 1H), 3.87 (m, 1H), 1.97 (m, 2H),1.43-1.70 (m, 6H). MS (ES): 398 [M+H]⁺.

Example 38 Compound of Formula (Z): R′=3-CF₃, R″=4-pyrrolidin-1-yl, andR′″=3-Cl

[0153] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),pyrrolidine (0.175 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 110° C. overnight. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to give product as a white solid (0.06 g, 52%).

[0154]¹H NMR (DMSO) δ 10.61 (s, 1H), 8.48 (s, 1H), 7.59 (s, 1H), 7.38(d, J=8.9 Hz, 1H), 7.07 (dd, J=8.3, 8.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H),6.80 (m, 2H), 6.50 (d, J=8.3 Hz, 1H), 3.35 (m, 4H), 1.89 (m, 4H). MS(ES): 384 [M+H]⁺.

Example 39 Compound of Formula (Z): R′=3CF₃, R″=4-piperidin-1-yl, andR′″=3-Cl

[0155] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),piperidine (0.208 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 130° C. for 24 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to yield product as a solid (0.05 g, 42%).

[0156]¹H NMR (DMSO) δ 10.85 (s, 1H), 8.62 (s, 1H), 7.64 (s, 1H), 7.58(d, J=8.3 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.08 (dd, J=8.6, 8.6 Hz, 1H),6.83 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 6.50 (d, J=8.3 Hz, 1H), 2.82 (m,4H), 1.61 (m, 4H), 1.52 (m, 2H). MS (ES): 398 [M+H]⁺.

Example 40 Compound of Formula (Z): R′=3-CF₃, R″=4-pyrrolin-lyl, andR′″=3-Cl

[0157] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),3-pyrroline (0.208 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 120° C. for 24 hrs. Purification was performed by flashchromatography on silica gel with 30% EtOAc/hexanes as eluent to yieldproduct as a solid (0.08 g, 87%).

[0158]¹H NMR (DMSO) δ 10.6 (s, 1H), 8.50 (s, 1H), 7.64 (s, 1H), 7.41 (d,J=8.9 Hz, 1H), 7.08 (dd, J=8.4, 8.4 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H),6.80 (m, 2H), 6.52 (d, J=7.6 Hz, 1H), 5.98 (s, 2H), 4.22 (s, 4H). MS(ES): 382 [M+H]⁺.

Example 41 Compound of Formula (Z): R′=3-CF₃, R″=4-benzylamino, andR′″=3-Cl

[0159] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),benzylamine (0.23 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 120° C. for 1.5 days. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to yield product as a white solid (0.08 g, 64%).

[0160]¹H NMR (DMSO) δ 10.50 (s, 1H), 8.41 (s, 1H), 7.45 (s, 1H),7.15-7.35 (m, 6H), 7.05 (dd, J=8.0, 8.0 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H),6.72 (s, 1H), 6.59 (dd, J=9.1, 9.1 Hz, 2H), 6.51 (d, J=8.3 Hz, 1H), 4.65(d, J=5.9 Hz, 2H). MS (ES): 420 [M+H]⁺.

Example 42 Compound of Formula (Z): R′=3-CF₃,R″=4-(tetrahydrofur-2-yl)amino, and R′″=3-Cl

[0161] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),tetrahydrofurylamine (0.217 ml, 2.1 mmol) and DMSO (1.2 ml). Thereaction was conducted at 130° C. for 1.5 days. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 35-45% EtOAc/hexanes to give product as a white solid (0.045 g, 36%).¹H NMR (DMSO) δ 10.54 (s, 1H), 8.45 (s, 1H), 7.45 (s, 1H), 7.36 (d,J=8.3 Hz, 1H), 7.07 (dd, J=8.3, 8.3 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H),6.78 (m, 2H), 6.51 (d, J=8.3 Hz 1H), 5.41 (m, 1H), 4.04 (m, 1H), 3.75(m,.1H), 3.63 (m, 1H), 3.29 (m, 1H), 3.18 (m, 1H), 1.75-2.0 (m, 3H),1.59 (m, 1H). MS (ES): 414 [M+H]⁺.

Example 43 Compound of Formula (Z): R′=3-CF₃,R″=4-(3-dimethylamino)propylamino, and R′″=3-Cl

[0162] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),3,3-dimethylaminopropylamine (0.264 ml, 2.1 mmol) and DMSO (1.2 ml). Thereaction was conducted at 130° C. for 1.5 days. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 2.5-5% NH₄OH in 30% MeOH/CH₂Cl₂ to give product as an oil (0.035 g,28%).

[0163]¹H NMR (DMSO) δ 10.51 (s, 1H), 8.44 (s, 1H), 7.44 (s, 1H), 7.37(d, J=8.3 Hz, 1H), 7.07 (dd, J=8.3, 8.3 Hz, 1H), 6.79 (m, 2H), 6.72 (m,2H), 6.51 (d, J=8.3 Hz, 1H), 3.21 (m, 2H), 2.38 (t, J=5.0 Hz, 2H), 2.16(s, 6H), 1.71 (m, 2H). MS (ES): 415 [M+H]⁺.

Example 44 Compound of Formula (Z): R′=3-CF₃, R″=4-azetidino, andR′″=3-Cl

[0164] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),azetidine (0.25 g, 4.38 mmol) and DMSO (1.2 ml). The reaction wasconducted at 110° C. for 18 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-40%EtOAc/hexanes to yield product as an oil (0.022 g, 20%).

[0165]¹H NMR (DMSO) δ 10.57 (s, 1H), 8.47 (s, 1H), 7.51 (s, 1H), 7.38(d, J=8.3 Hz, 1H), 7.07 (dd, J=8.3, 8.3 Hz, 1H), 6.79 (m, 2H), 6.51 (m,2H), 4.02 (m, 4H), 2.26 (m, 2H). MS (ES): 370 [M+H]⁺.

Example 45 Compound of Formula (Z): R′=3-CF₃, R″=4-[(R)-(+)-3-hydroxy]pyrrolidin-1-yl, and R′″=3-Cl

[0166] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),(R)-(+)-3-pyrrolidinol (0.175 ml, 2.1 mmol) and DMSO (1.2 ml). Thereaction was conducted at 120° C. overnight. Purification was performedby flash chromatography on silica gel with a gradient elution of 60-80%EtOAc/hexanes to yield product as a white solid (0.09 g, 75%).

[0167]¹H NMR (DMSO) δ 10.60 (s, 1H), 8.48 (s, 1H), 7.59 (s, 1H), 7.37(d, J=8.3 Hz, 1H), 7.08 (dd, J=8.4, 8.4 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H),6.80 (m, 2H), 6.50 (d, J=8.3 Hz, 1H), 4.97 (d, J=3.4 Hz, 1H), 4.35 (s,1H, broad), 3.52 (m, 2H), 3.29 (m, 1H), 3.11 (d, J=11.1 Hz, 1H), 1.96(m, 1H), 1.85 (m, 1H). MS (ES): 400 [M+H]⁺.

Example 46 Compound of Formula (Z): R′=3-CF₃, R″=4-cyclopropylmethylamino, and R′″=3-Cl

[0168] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),cyclopropylmethyl amine (0.182 ml, 2.1 mmol) and DMSO (1.2 ml). Thereaction was conducted at 130° C. for 20 hrs. Purification was performedby flash chromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to give rpoduct as an oil (0.08 g, 69%).

[0169]¹H NMR (DMSO) δ 10.52 (s, 1H), 8.44 (s, 1H), 7.44 (s, 1H), 7.37(d, J=8.3 Hz, 1H), 7.08 (dd, J=8.3, 8.3 Hz, 1H), 6.81 (m, 3H), 6.80 (m,2H), 6.52 (d, J=8.3 Hz, 1H), 5.58 (m, 1H), 4.35 (s, 1H, broad), 3.52 (m,2H), 3.07 (m, 2H), 1.09 (m, 1H), 0.43 (m, 2H), 0.24 (m, 2H). MS (ES):384 [M+H]⁺.

Example 47 Compound of Formula (Z): R′=3-CF₃,R″=4-(3-hydroxy)propylamino, and R′″=3-Cl

[0170] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),3-amino-1-propanol (0.161 ml, 2.1 mmol) and DMSO (1.2 ml). The reactionwas conducted at 130° C. for 20 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 60-90%EtOAc/hexanes to yield product as a white solid (0.07 g, 60%).

[0171]¹H NMR (DMSO) δ 10.51 (s, 1H), 8.44 (s, 1H), 7.44 (s, 1H), 7.38(d, J=8.3 Hz, 1H), 7.08 (dd, J=8.3, 8.3 Hz, 1H), 6.79 (m, 3H), 6.80 (m,2H), 6.51 (d, J=8.3 Hz, 1H), 5.88 (m, 1H), 4.65 (m, 1H), 3.50 (m, 2H),3.25 (m, 2H), 1.70 (m, 2H). MS (ES): 388 [M+H]⁺.

Example 48 Compound of Formula (Z): R′=3-CF₃,R″=4-(2-methoxyethyl)amino, and R′″=3-Cl

[0172] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),2-methoxyethylamine (0.183 ml, 2.1 mmol) and DMSO (1.2 ml). The reactionwas conducted at 130° C. for 20 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 45-60%EtOAc/hexanes to yield the title compound as a white solid (0.065 g,56%).

[0173]¹H NMR (DMSO) δ 10.54 (s, 1H), 8.45 (s, 1H), 7.44 (s, 1H), 7.38(d, J=8.3 Hz, 1H), 7.08 (dd, J=8.3, 8.3 Hz, 1H), 6.81 (m, 3H), 6.51 (d,J=8.3 Hz, 1H), 5.48 (m, 1H), 3.49 (t, J=5.4 Hz, 2H), 3.36 (m, 2H), 3.27(s, 3H). MS (ES): 388 [M+H]+.

Example 49 Compound of Formula (Z): R′=3-CF₃,R″=4-(3-methylamino)pyrrolidin-1-yl, and R′″=3-Cl

[0174] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),3-methylaminopyrrolidine (0.224 ml, 2.1 mmol) and DMSO (1.2 ml). Thereaction was conducted at 100° C. overnight. Purification was performedby flash chromatography on silica gel with a gradient elution of 0-5%NH₄OH in 30% MeOH/CH₂Cl₂ to yield the title compound as a white solid(0.05 g, 40%).

[0175]¹H NMR (DMSO) δ 10.62 (s, 1H), 8.49 (s, 1H), 7.59 (s, 1H), 7.39(d, J=8.3 Hz, 1H), 7.08 (dd, J=8.3, 8.3 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H),6.80 (m, 2H), 6.50 (d, J=8.3 Hz, 1H), 3.1-3.55 (m, 6H), 2.31 (s, 3H),2.05 (m, 1H), 1.80 (m, 1H). MS (ES): 413 [M+H]⁺.

Example 50 Compound of Formula (Z): R′=3-CF₃, R″=4-propylamino, andR′″=3-Cl

[0176] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),propylamine (0.173 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 130° C. overnight. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to yield the title compound as an oil (0.05 g, 45%).

[0177]¹H NMR (DMSO) δ 10.51 (s, 1H), 8.43 (s, 1H), 7.43 (s, 1H), 7.36(d, J=8.3 Hz, 1H), 7.07 (dd, J=8.3, 8.3 Hz, 1H), 6.77 (m, 3H), 6.52 (d,J=8.3 Hz, 1H), 5.64 (m, 1H), 3.15 (m, 2H), 1.53 (m, 2H), 0.87 (t, J=7.4Hz, 3H). MS (ES): 372 [M+H]+.

Example 51 Compound of Formula (Z): R′=3-CF₃,R″=4-(3-amino)pyrrolidin-1-yl, and R′″=3-Cl

[0178] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),3-aminopyrrolidine (0.173 ml, 2.1 mmol) and DMSO (1.2 ml). The reactionwas conducted at 100° C. for 20 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 0-5% NH₄OH in30% MeOH/CH₂Cl₂ to yield the title compound as a white solid (0.075 g,63%).

[0179]¹H NMR (DMSO) δ 10.60 (s, 1H), 8.48 (s, 1H), 7.58 (s, 1H), 7.38(d, J=8.3 Hz, 1H), 7.08 (dd, J=8.3, 8.3 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H),6.80 (m, 2H), 6.51 (d, J=8.3 Hz, 1H), 3.50 (m, 3H), 3.28 (m, 3H), 3.04(m, 1H), 2.03 (m, 1H), 1.70 (m, 1H). MS (ES): 399 [M+H]⁺.

Example 52 Compound of Formula (Z): R′=3-CF₃,R″=4-(3-hydroxy)pyrrolidin-1-yl, and R′″=3-Cl

[0180] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),3-pyrrolidinol (0.175 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 100° C. for 20 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 60-80%EtOAc/hexanes to yield the title compound as a white solid (0.083 g,69%).

[0181]¹H NMR (DMSO-d₆): δ 10.60 (s, 1H), 8.48 (s, 1H), 7.58 (s, 1H),7.38 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.4, 8.4 Hz, lIH), 6.94 (d, J=9.0Hz, 1H), 6.80 (m, 2H), 6.51 (d, J=8.3 Hz, 1H), 4.96 (s, 1H), 4.35 (s,1H, broad), 3.54 (m,. 2H), 3.29 (m, 1H), 3.11 (d, J=11.1 Hz, 1H), 1.96(m, 1H), 1.84 (m, 1H). MS (ES): 400 [M+H]⁺.

Example 53 Compound of Formula (Z): R′=3-CF₃, R″=4-pentylamino, andR′″=3-Cl

[0182] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),n-pentylamine (0.243 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 130° C. overnight. Purification was performed by flashchromatography on silica gel with 30% EtOAc/hexanes to yield the titlecompound as an oil (0.083 g, 69%).

[0183]¹H NMR (DMSO) δ 10.51 (s, 1H), 8.44 (s, 1H), 7.43 (s, 1H), 7.37(d, J=8.3 Hz, 1H), 7.07 (dd, J=8.4, 8.4 Hz, 1H), 6.77 (m, 3H), 6.52 (d,J=8.3 Hz, 1H), 4.96 (s, 1H), 3.61 (m, 1H), 3.17 (m, 2H), 1.51 (m, 2H),1.29 (m, 4H), 0.86 (t, J=6.8 Hz, 3H). MS (ES): 400 [M+H]⁺.

Example 54 Compound of Formula (Z): R′=3-CF₃, R″=4-allylamino, andR′″=3-Cl

[0184] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),allylamine (0.158 ml, 2.1 mmol) and DMSO (1.2 ml). The reaction wasconducted at 130° C. overnight. Purification was performed by flashchromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to yeild the title compound as an oil (0.08 g, 72%).

[0185]¹H NMR (DMSO) δ 10.52(s, 1H), 8.44 (s, 1H), 7.44 (s, 1H), 7.34 (d,J=8.3 Hz, 1H), 7.07 (dd, J=8.1, 8.1 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H),6.75 (s, 1H), 6.68 (d, J=9.0 Hz, 1H), 6.52 (d, J=8.3 Hz, 1H), 6.04 (t,J=5.5 Hz, 1H), 5.82 (m, 1H), 5.10 (m, 2H), 3.86 (m, 2H). MS (ES): 370[M+H]⁺.

Example 55

[0186] Compound of Formula (Z): R′=3-CF₃,R″=4-(1,2,3,6-tetrahydro)pyridin-1-yl, and R′″=3-Cl

[0187] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),1,2,3,6-tetrahydropyridine (0.192 ml, 2.1 mmol) and DMSO (1.2 ml). Thereaction was conducted at 130° C. for 24 hrs. Purification was performedby flash chromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to yield the title compound as a white solid (0.035 g,30%).

[0188]¹H NMR (DMSO) δ 10.86 (s, 1H), 8.63 (s, 1H), 7.67 (s, 1. H), 7.58(d, J=8.3 Hz, 1H), 7.07 (dd, J=8.1, 8.1 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H),6.76 (s, 1H), 6.52 (d, J=8.3 Hz, 1H), 5.80 (m, 2H), 3.42 (m, 2H), 2.99(m, 2H), 2.18 (m, 2H). MS (ES): 396 [M+H]⁺.

Example 56 Compound of Formula (Z): R′=3-CF₃, R″=4-[(R)-3-trifluoroacetomido]pyrrolidin-1-yl, and R′″=3-Cl

[0189] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),(3R)-(+)-3-(trifluoroacetamido)pyrrolidine hydrochloride (0.459 g, 2.1mmol), NEt₃ (0.585 ml, 4.2 mmol) and DMSO (2 ml). The reaction wasconducted at 100° C. for 18 hrs. Purification was performed by flashchromatography on silica gel with a gradient elution of 40-60%EtOAc/hexanes to give the title compound as a white solid (0.02 g, 13%).

[0190]¹H NMR (DMSO) δ 10.65 (s, 1H), 9.66 (d, J=6.7 Hz, 1H), 8.51 (s,1H), 7.61 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.07 (dd, J=8.1, 8.1 Hz, 1H),7.00 (d, J=8.2 Hz, 1H), 6.80 (m, 2H), 6.51 (d, J=8.3 Hz, 1H), 4.41 (m,1H), 3.60 (m, 1H), 3.3-3.5 (m, 3H), 2.20 (m, 1H), 2.02 (m, 1H). MS (ES):495 [M+H]⁺.

Example 57 Compound of Formula (Z): R′=3-CF₃, R″=4-pyrrol-1-yl, andR′″=3-Cl

[0191] A sample compound from Example 19 (0.033 g, 0.1 mmol),2,5-dimethoxytetrahydrofuran (0.065 ml, 0.5 mmol) and HOAc (1 ml) washeated to 70° C. for 45 min. The mixture was allowed to cool to roomtemperature, poured into sat. NaHCO₃ and extracted with EtOAc. Theorganic layer was separated, washed with brine, dried with anhydrousNa₂SO₄, concentrated by rotary evaporation and purified by flashchromatography on silica gel with a gradient elution of 30-35%EtOAc/hexanes to give the title compound as an oil (0.03 g, 79%).

[0192]¹H NMR (DMSO) δ 11.11 (s, 1H), 8.76 (s, 1H), 7.88 (s, 1H), 7.73(d, J=8.3 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.11 (dd, J=8.2, 8.2 Hz, 1H),6.93 (m, 2H), 6.87 (m, 2H), 6.53 (d, J=8.2 Hz, 1H), 6.24 (m, 2H). MS(ES): 380 [M+H]⁺.

Example 58 Compound of Formula (Z): R′=3-CF₃, R″=4-[(R)-3-acetomido]pyrrolidin-1-yl, and R′″=Cl

[0193] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),3-(N-acetyl-N-methylamino)pyrrolidine (0.269 g, 2.1 mmol) and DMSO (1.2ml). The reaction was conducted at 120° C. for 18 hrs. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 0-10% MeOH/EtOAc to yield the title compound as a white solid (0.103g, 78%).

[0194]¹H NMR (DMSO) δ 10.62 (s, 1H), 8.49 (s, 1H), 8.10 (d, J=5.6 Hz,1H), 7.60 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.07 (dd, J=8.1, 8.1 Hz, 1H),6.96 (d, J=8.2 Hz, 1H), 6.80 (m, 2H), 6.51 (d, J=8.3 Hz, 1H), 4.27 (m,1H), 3.55 (m, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 3.15 (m, 1H), 2.10 (m,1H), 1.83 (m, 1H), 1.80 (s, 1H). MS (ES): 441 [M+H]⁺.

Example 59 Compound of Formula (Z): R′=3-CF₃, R″=4-cyclopropylamino, andR′″=3-Cl

[0195] Synthesized according to the same procedure as was used forExample 22 starting from the compounds of Example 17 (0.1 g, 0.3 mmol),cyclopropylamine (0.146 ml, 2.1 mmol) and DMSO (1.2 ml). The reactionwas conducted at 120° C. for 2 days. Purification was performed by flashchromatography on silica gel with a gradient elution of 60-80%EtOAc/hexanes to give the title compound as a white solid (0.05 g, 45%).

[0196]¹H NMR (DMSO) δ 10.56 (s, 1H), 8.46 (s, 1H), 7.44 (m, 2H), 7.60(s, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.08 (dd, J=8.1, 8.1 Hz, 1H), 6.79 (m,2H), 6.51 (d, J=8.3 Hz, 1H), 5.99 (s, 1H), 2.42 (m, 1H), 0.75 (m, 2H),0.50 (m, 2H). MS (ES): 370 [M+H]⁺.

Example 60 Compound of Formula (Z): R′=3-CF₃, R″=4-cyclopentylthio, andR′″=3-Cl

[0197] A sample of the compound from Example 17 (0.1 g, 0.3 mmol),cyclopentyl mercaptan (0.225 ml, 2.1 mmol), NaHCO₃ (0.14 g) and DMSO(1.2 ml) was heated to 90° C. overnight. The mixture was allowed to coolto room temperature, poured into brine and extracted with EtOAc. Theorganic layer was separated, washed with brine, dried with anhydrousNa₂SO₄, concentrated by rotary evaporation and purified by flashchromatography on silica gel with 30% EtOAc/hexanes to yield the titlecompound as a white solid (0.128 g, 100%).

[0198]¹H NMR (DMSO) δ 10.93 (s, 1H), 8.67 (s, 1H), 7.70 (s, 1H), 7.63(d, J=8.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.08 (dd, J=8.1, 8.1 Hz, 1H),6.83 (d, J=8.2 Hz, 1H), 6.77 (s, 1H), 6.51 (d, J=8.3 Hz, 1H), 3.84(quint, J=6.3 Hz, 1H), 2.09 (m, 2H), 1.70 (m, 2H), 1.58 (m, 2H), 1.50(m, 2H). MS (ES): 415 [M+H]⁺.

Example 61 Compound of Formula (Z): R′=3-CF₃, R″=4-isopropylthio, andR′″=3-Cl

[0199] Synthesized according to the same procedure used for Example 60starting from a sample of compound from Example 22 (0.08 g, 0.24 mmol),2-propanethiol (0.156 ml, 1.68 mmol), NaHCO₃ (0.115 g) and DMSO (1 ml).The reaction was conducted at 90° C. overnight. Purification wasperformed by flash chromatography on silica gel with a gradient elutionof 35-40% EtOAc/hexanes to give the title compound as a white solid(0.073 g, 78%).

[0200]¹H NMR (DMSO) δ 10.95 (s, 1H), 8.70 (s, 1H), 7.72 (s, 1H), 7.66(d, J=8.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.09 (dd, J=8.1, 8.1 Hz, 1H),6.84 (d, J=8.2 Hz, 1H), 6.74 (s, 1H), 6.51 (d, J=8.3 Hz, 1H), 3.68(sept, J=6.3 Hz, 1H), 1.25 (d, J=6.6 Hz, 1H). MS (ES): 389 [M+H]⁺.

Example 62 Compound of Formula (Z): R′=3-CF₃, R″=4-ethylthio, andR′″=3-Cl

[0201] Synthesized according to the same procedure used for Example 60starting from a sample of compound from Example 22 (0.08 g, 0.24 mmol),ethanethiol (0.125 ml, 1.68 mmol), NaHCO₃ (0.115 g) and DMSO (1 ml). Thereaction was conducted at 90° C. overnight. Purification was performedby flash chromatography on silica gel with a gradient elution of 35-40%EtOAc/hexanes to yield the title compound as a white solid (0.073 g,78%).

[0202]¹H NMR (DMSO) δ 10.92 (s, 1H), 8.70 (s, 1H), 7.70 (s, 1H), 7.56(m, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.78 (s, 1H),6.74 (s, 1H), 6.51 (d, J=8.3 Hz, 1H), 3.08 (q, J=7.3 Hz, 2H), 1.23 (dt,J=7.3 Hz, 1H). MS (ES): 375 [M+H]⁺.

Example 63 Compound of Formula (Z): R′=3-Cl, R″=4-Cl, and R′″=4-F

[0203] The title compound was prepared following procedures describedfor Example 1 except substituting 3,4-dichlorobenzoyl chloride for3-trifluoromethylbenzoyl chloride and substituting 4-flroroaniline foraniline. ¹H NMR (CDCl₃) δ 7.54 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.3 Hz,1H), 7.14 (dd, J=2.0 Hz, J=8 Hz, 1H), 6.86 (m, 2H), 6.67 (m, 2H). MS(ES+): 299 (M+H, 100).

Example 64 Compound of Formula (Z): R′=3-CF₃, R″=4-Cl, and R′″=3-Cl

[0204] Step 64a. 4-Chloro-3-trifluoromethylbenzaldehyde (0.315 g, 1.51mmol, purchased from Aldrich Chemical Co.) and hydroxyaminehydrochloride (0.315 g, 4.53 mmol) were stirred in methanol (5 mL) at 0°C. for 1 h. The reaction mixture was diluted with ethyl acetate and waswashed with water and saturated NaCl solution. Organic layer was driedwith Na2SO4, filtered and concentrated to give the oxime intermediate.

[0205] Step 64b. The oxime was dissolved in DMF(3 mL) and was treatedwith N-bromosucinimide (0.325 g, 1.83 mmol) at 0° C. The starting oximereacted completely in one hour, at which time excess 3-chloroaniline (5equiv.) and triethylamine (3 equiv.) were added. Stir continued at 0° C.overnight. The reaction mixture was diluted with ethyl acetate and waswashed with water and saturated NaCl solution. Organic layer was driedover MgSO₄, filtered, and concentrated. The crude product was purifiedby flash chromatography on silica gel eluted with 6:1 to 3:1hexane/AcOEt to give pure product, 51.5 mg, in 10% yield.

[0206]¹H (DMSO) δ 11.1 (s, 1H), 8.75 (s, 1H), 7.83 (s, 1H), 7.70 (d,J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 6.85 (d,J=8.0 Hz, 1H), 6.82 (s, 1H), 6.50 (d, J=8.0Hz, 1H). MS (ES): 350 [M+H]⁺.

Example 65 Compound of Formula (Z): R′=3-CF₃, R″=4-Cl, and R′″=H

[0207] Following procedures described for Example above and substituting3-chloroaniline with aniline in Step 64b, the title compound wasobtained in 11.5% yield.

[0208]¹H (DMSO) δ 10.9 (s, 1H), 8.5 (s, 1H), 7.77 (s, 1H), 7.67 (d,J=8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.11 (t, J=7.4 Hz, 2H), 6.83 (t,J=7.4 Hz, 1H), 6.67 (d, J=7.4 Hz, 2H). MS (ES): 315 [M+H]⁺.

Example 66 Compound of Formula (Z): R′=3-OCF₂CHF₂, R″=H, and R′″=3-Cl

[0209] The title compound was synthesized following procedures describedfor Example 1 except substituting 3-tetrafluoroethoxybenzoyl chloridefor 3-trifluoromethylbenzoyl chloride and substituting 3-chloroanilinefor aniline. ¹H NMR (DMSO) δ 10.9 (s, 1H), 8.66 (s, 1H), 7.47 (t, J=7.8Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.24 (s, 1H),7.07 (t, J=8.0 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.76 (t, J=55 Hz, 1H),6.73 (s, 1H), 6.50 (d, J=8.0 Hz, 1H). MS (ES): 363 [M+H]⁺.

Example 67 Compound of Formula (Z): R′=3-OCF₂CHF₂, R″=H, and R′″=3-F

[0210] The title compound was synthesized following procedures describedfor Example 1 except substituting 3-tetrafluoroethoxybenzoyl chloridefor 3-trifluoromethylbenzoyl chloride and substituting 3-fluroanilinefor aniline.

[0211]¹H NMR (DMSO): δ 10.9 (s, 1H), 8.65 (s, 1H), 7.44 (t, J=8.0 Hz,1H), 7.38 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.22 (s, 1H), 7.08(q, J=7.8 Hz, 1H), 6.75 (t, J=50 Hz, 1H), 6.59 (dd, J=7.8, 7.6 Hz, 1H),6.45 (d, J=7.8 Hz, 1H), 64.2 (d, J=7.6 Hz, 1H). MS (ES): 347 [M+H]⁺.

Example 68 Compound of Formula (Z): R′=3-Br, R″=H, and R′″=H

[0212] Following procedures described in Example 1 and substituting3-bromobenzoyl chloride for 3-trifluoromethylbenzoyl chloride the titlecompound was prepared in 30% yield.

[0213]¹H NMR (DMSO) δ 10.7 (s, 1H), 8.36 (s, 1H), 7.53 (m, 2H), 7.29 (m,2H), 7.09 (dd, J=8.0, 8.0 Hz, 2H), 6.81 (dd, J=8.1, 8.1 Hz, 1H), 6.65(d, J=7.5 Hz, 2H). MS (ES): 291 [M+H]⁺.

Example 69 Compound of Formula (Z): R′=3-phenyl, R″=H, and R′″=H

[0214] General procedures for Suzuki coupling of the compound fromExample 68 and the respective boronic acid: To a flask containing aq.K2CO3 (0.4 ml, 2.0 M), EtOH (0.2 ml) and toluene (2 ml) was added asample of compound of Example 68 (0.136 g, 0.5 mmol), PhB(OH) 2 (0.091g, 0.75 mmol) and Pd(PPh3)₄ (0.115 g, 0.1 mmol). The mixture was stirredfor 2 hrs at 1000C under a nitrogen atmosphere. It was then cooled tor.t. and poured into water. The mixture was extracted with EtOAc. Theorganic layer was separated, washed with brine, dried with anhydrousNa2SO4, concentrated by rotary evaporation and purified by flashchromatography on silica gel with a gradient elution of 25-35%EtOAc/hexanes to yield the title compound as a white solid (0.085 g,59%). 1H NMR (DMSO) δ 10.58 (s, 1H), 8.34 (s, 1H), 7.63 (d, J=10.0 Hz,1H), 7.60 (s, 1H), 7.50 (d, J=7.0 Hz, 2H), 7.38 (m, 5H), 7.06 (m, 2H),6.79 (m, 1H), 6.71 (d, J=7.56,2H). MS (ES): 289 [M+H]⁺.

Example 70 Compound of Formula (Z): R′=3-pyrid-3-yl, R″=H, and R′″=H

[0215] Synthesized according to the same procedure used Example 69starting from a sample of compound of Example 68 (0.136 g, 0.5 mmol),aq. K₂CO₃ (0.4 ml, 2.0M), pyridine-3-boronic acid (0.092 g, 0.75 mmol)and Pd(PPh₃)₄ (0.155 g, 0.14 mmol) in EtOH (0.2 ml) and toluene (2 ml).The mixture was stirred overnight under a nitrogen atmosphere at 100° C.Purification was performed by flash chromatography on silica gel withEtOAc as the eluent to yield the title compound as a white solid (0.040g, 28%).

[0216]¹H NMR (DMSO) δ 10.61 (s, 1H), 8.70 (s, 1H), 8.55 (d, J=4.4 Hz,1H), 8.37 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.64(s, 1H), 7.43(m, 3H), 7.07 (dd, J=8.3, 8.3 Hz, 2H), 6.79 (dd, J=7.7, 7.7Hz, 1H), 6.71 (d, J=7.6 Hz, 2H). MS (ES): 290 [M+H]⁺.

Example 71 Compound of Formula (Z): R′=3-naphthal-2-yl, R″=H, and R′″=H

[0217] Synthesized according to the same procedure used Example 69starting from a sample of compound of Example 68 (0.136 g, 0.5 mmol),aq. K₂CO₃ (0.4 ml, 2.0M), 2-naphthaleneboronic acid (0.129 g, 0.75 mmol)and Pd(PPh₃)₄ (0.055 g, 0.05 mmol) in EtOH (0.2 ml) and toluene (2 ml).The mixture was stirred under a nitrogen atmosphere for 1.5 hrs at 100°C. Purification was performed by flash chromatography on silica gel witha gradient elution of 30-45% EtOAc/hexanes to give the title compound asawhite solid (0.065 g, 38%).

[0218]¹H NMR (DMSO) δ 10.60 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.95(m, 3H), 7.76 (m, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.53 (m, 2H), 7.46 (dd,J=7.4, 7.4 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H),7.10 (dd, J=7.6, 7.6 Hz, 2H),6.80 (dd, J=7.6, 7.6 Hz, 1H), 6.74 (d, J=7.8 Hz, 2H). MS (ES): 339[M+H]⁺.

Example 72 Compound of Formula (Z): R′=3-CF₃, R″=4-propyn-1-yl, andR′″=3-Cl

[0219] Step 72a. The N-3-chlorophenyl 4-azido-3-trifluoromethylbenzamidecompound from Step 18c was reduced under 1 atm of hydrogen in thepresence of Pd/in ethanol to the give the corresponding4-aminobenzamide, which was used without purification in Step 72b.

[0220] Step72b. 4-Amino-N-(3-chlorophenyl)-3-trifluoromethylbenzamide(5.25 g, 16.7 mmol) was suspended in a solution of methanol/water 1:1(400 mL) and cooled to −10° C. Next, concentrated HCl (20 mL) was addedfollowed by a dropwise addition of an aqueous solution of NaNO₂(1.50 g,21.7 mmol). After stirring for 45 min. at −10° C., an aqueous solutionof sodium iodide (3.51 g, 23.4 mmol) was added dropwise, and thesolution was allowed to slowly warm to room temperature over a period of2 h. The dark solution was then extracted with ether, washed with asaturated solution of Na₂S₂O₃, brine, and dried over Na₂SO₄. Excesssolvent was removed using reduced pressure, and the remaining materialwas purified using flash chromatography (silica) eluting with a 4:1solution of hexane and ethyl actetate. Similar fractions were pooled andconcentrated to give 3.2 g (45%) of corresponding 4-iodo product(off-white solid). MS (ES+): 426 (M+H, 100).

[0221] Step 72c. A general procedure for the Negishi cross coupling.Under an atomosphere of nitrogen, a THF solution of zinc bromide (10eq.) was added dropwise to a solution of Grignard reagent (10 eq.) atroom temperature. After stirring for 2 h, the aryl iodide (1 eq.) fromStep 72c was added followed by the addition of (Dppf)₂PdCl₂ (0.05 eq.).The solution was then allowed to stir overnight at room temperature. Thereaction was quenched with a saturated sol of NH₄Cl, and the resultingmixture was extracted with ether, washed with brine, and dried overNa₂SO₄. Excess solvent was removed using reduced pressure, and theresulting residue was purified on silica eluting with a 20% ethylacetate/hexane solution. Starting with propynyl Grignard the titlecompound was obtained.

[0222]¹H NMR (CDCl₃) δ 8.59 (s, 1H), 7.74 (s, 1H), 7.41 (m, 2H), 7.19(s, 1H), 7.01 (t, J=8 Hz, 1H), 6.92 (m, 1H), 6.73 (t, J=2 Hz, 1H), 6.43(m1 H), 2.08 (s, 3H). MS (ES+): 353(M+H, 100).

Example 73 Compound of Formula (Z): R′=3-CF₃, R″=4-vinyl, and R′″=3-Cl

[0223] The title compound was prepared following conditions of Step 72cof Example 72 except using vinyl Grignard.

[0224]¹H NMR (CDCl₃) δ 7.73 (d, J=6.2 Hz, 1H), 7.53-7.64 (m, 1H),7.42-7.49 (m, 1H), 7.02 (m, 2H), 6.94 (m, 1H), 6.75 (dt , J=2.1 Hz,J=18.4 Hz, 1H), 6.46 (m, 1H), 5.78 (d, J=17.3 Hz, 1H), 5.45 (d, J=11.5Hz, 1H). MS (ES+): 341 (M+H, 100).

Example 74 Compound of Formula (Z): R′=3-CF₃,R″=4-(2-methyl)prop-1-enyl, and R′″=3-Cl

[0225] The title compound was prepared following conditions of Step 72cof Example 72 except using 2-methylbutenyl Grignard.

[0226]¹H NMR (CDCl₃) δ 7.75 (s, 1H), 7.43 (d, J=8 Hz, 1H), 7.26 (s, 1H),7.20 (d, J=8.0 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.91 (m, 1H), 6.69 (t,J=2.0 Hz, 1H), 6.48 (m, 1H), 6.37 (s, 1H). MS (ES+): 369 (M+H, 100).

Example 75 Compound of Formula (Z): R′=3-CF₃, R″=4-isobutyl, andR′″=3-Cl

[0227] A sample of the compound from Example 74 was hydrogenated under 1atm of H₂ and in the presence of Pd/C to give the title compound.

[0228]¹H NMR (CDCl₃) δ 7.73 (d, J=1.4 Hz, 1H), 7.41 (dd, J=1.4Hz, J=8.0Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 6.91 (dm, J=8Hz, 1H), 6.66 (t, J=2.0 Hz, 1H), 6.47 (dm, J=8.1 Hz, 1H), 2.63 (d, J=7.3Hz, 2H), 1.92 (qn, J=6.8 Hz, 1H), 0.88 (d, J=6.6 Hz, 6H). MS (ES+): 371(M+H, 100).

Example 76 Compound of Formula (Z): R′=3-CF₃, R″=4-allyl, and R′″=3-Cl

[0229] The title compound was prepared following conditions of Step 72cof Example 72 and using allyl Grignard.

[0230]¹H NMR (CDCl₃) δ 7.72 (s, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.33 (s,1H), 7.28 (d, J=8 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.95 (dm, J=8.0 Hz,1H), 6.73 (t, J=2.0 Hz, 1H), 6.49 (dm, J=8.0 Hz), 5.89 (m, 1H), 5.11(dd, J=1.4 Hz, J=10 Hz, 1H), 5.02 (dd, J=1.5 Hz, J=17 Hz, 1H), 3.53 (d,J=6.3 Hz, 2H). MS (ES+): 355 (M+H, 100).

Example 77

[0231]

[0232] Benzothiophene-2-carboxylic acid was treated with 1.5 equivalentsof oxalyl chloride in dichloromethane in the presence of a catalyticamount of DMF to form benzothiophene-2-carbonyl chloride. Followingprocedures described for Example 1 and substituting this acyl chloridefor 3-trifluoromethylbenzoyl chloride, compound 77 was prepared in 23%yield.

[0233]¹H NMR (DMSO) δ 10.94 (s, 1H), 8.41 (s, 1H), 7.91 (d, J=8.4 Hz,1H), 7.74 (d, J=8.6 Hz, 1H), 7.34 (m, 2H), 7.29 (s, 1H), 7.14 (t, J=7.2Hz, 1H), 6.82 (m, 3H). MS (ES+): 269 (M+H), MS (ES−): 267 (M−H). Anal.Calcd. for C₁₅H₁₂N₂OS: C, 67.14; H, 4.51; N, 10.44; S, 11.95. Found: C,65.83; H, 4.51; N, 10.15; S, 11.67.

Example 78

[0234]

[0235] Compound 78 was synthesized in a manner similar to compound 77.

[0236]¹H NMR (CDCl₃) δ 9.17 (s, 1H), 7.63 (d, J=1.8 Hz, 1H) 7.36 (s,1H), (dd, J=1.5 Hz, J=6.5 Hz, 1H), 7.05 (t, J=8 Hz, 2H), 6.94 (t, J 8Hz, 2H), 6.62 (d, J=7.5 Hz, 2H), MS (ES+): 366(M+H, 100).

Example 79

[0237]

[0238] Compound 79 was synthesized in a manner similar to compound 77.

[0239]¹H NMR (CDCl₃) δ 9.24 (s, 1H), 7.64 (s, 1H), 7.24 (m, 2H), 7.02(d, J=8.7 Hz, 1H), 6.95 (t, J=8.0 Hz, 1H), 6.89 (dm, J=8.0 Hz, 1H),6.75(s, 1H), 6.46 (dm, J=7.9 Hz, 1H). MS (ES+): 400 (M+H, 100).

Example 80

[0240]

[0241] Compound 80 was synthesized in a manner similar to compound 77.

[0242]¹H NMR (CDCl₃) δ 7.61(d, J=2.0 Hz, 1H), 7.37 (dd, J=2.0 Hz, J=8.5Hz, 1H), 7.20-7.28 (m, 3H), 7.05 (t, J=7.0 Hz, 1H), 6.86 (d, J=7.6 Hz,2H), 6.60 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H). MS (ES+): 358 (M+H,100).

Example 81

[0243]

[0244] Compound 81was synthesized in a manner similar to compound 77.

[0245]¹H NMR (DMSO) δ 10.7 (s, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 7.75 (d,J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 6.95 (t, J=8.5 Hz, 2H), 6.75 (t,J=8.5 Hz, 1H), 6.52 (d, J=8.5 Hz, 2H), 1.72 (s, 3H). MS (ES+): 343 (M+H,100).

Example 82

[0246]

[0247] Compound 82 was synthesized in a manner similar to compound 77.

[0248]¹H NMR (DMSO) δ 10.6 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.88 (d,J=8.3 Hz, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.51 (m, 2H), 7.45 (d, J=8.5 Hz,1H), 7.02 (t, J=8.0 Hz, 2H), 6.75 (t, J=7.8 Hz, 1H), 6.68 (d, J=7.6 Hz,2H). MS (ES+): 263 (M+H), MS (ES−): 261 (M−H). Anal. Calcd. forC₁₇H₄₁N₂O: C, 77.84; H, 5.38; N, 10.68. Found: C, 77.73; H, 5.68; N,10.19.

Example 83

[0249]

[0250] Compound 83 was synthesized in a manner similar to compound 77.

[0251]¹H NMR (DMSO) δ 10.8 (s, 1H), 8.82 (s, 1H), 7.97 (d, J=8.0 Hz,1H), 7.77 (d, J=8.4 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.06 (t, J=7.7 Hz,1H), 6.80 (t, J=7.7 Hz, 1H), 6.70 (d, J=7.7 Hz, 2H). MS (ES+): 263[M+H]⁺.

Example 84

[0252]

[0253] Compound 84 was synthesized in a manner similar to compound 77.

[0254]¹H NMR (DMSO) δ 10.7 (s, 1H), 8.30 (s, 1H), 7.88 (s, 1H), 7.85 (d,J=7.5 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.58 (d,J=7.5 Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.08 (d, J=17 Hz, 1H), 6.95 (s,1H), 6.85 (d, J=17 Hz, 1H), 6.81 (d, J=7.2 Hz, 1H).

Example 85

[0255]

[0256] Compound 85 was synthesized in a manner similar to compound 77.

[0257]¹H NMR (DMSO) δ ¹H NMR (DMSO) δ 10.8 (s, 1H), 8.63 (s, 1H), 7.42(s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.08 (q, J=7.8Hz, 1H), 6.59 (t, J=7.5 Hz, 1H), 6.50 (d, J=11.2 Hz, 1H), 6.38 (d, J=7.8Hz, 1H). MS (ES+): 311 [M+H]⁺.

Example 86

[0258]

[0259] Compound 86 was synthesized in a manner similar to compound 77.

[0260]¹H NMR (DMSO) δ ¹H NMR (DMSO) δ 10.9 (s, 1H), 8.63 (s, 1H), 7.43(s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.05 (t, J=8.0Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.80 (s, 1H), 6.48 (d, J=8.0 Hz, 1H).MS (ES+): 327 [M+H]⁺.

Example 87

[0261]

[0262] The title compound was prepared in 76% yield following methodsdeveloped for Example 1 except substituting methoxyamine hydrochloridefor hydroxyamine hydrochloride in Step 1b.

[0263]¹H NMR (DMSO) δ 8.70 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.64 (s,1H), 7.58 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.09 (t, J=7.5 Hz,2H), 6.85 (t, J=7.5 Hz, 1H), 6.68 (t, 7.5 Hz, 2H), 3.87 (s, 3H). MS(ES+): 295 [M+H]⁺.

Example 88

[0264]

[0265] Step 88a. To a dichloroethane solution of7-pyrrolidin-1-yl-benzofaran-2-carboxylic acid (3-chloro-phenyl)-amide(343 mg, 1 μM) was added phosphorous pentachloride (210 mg, 1.2 mmol),and the mixture was stirred at 75° C. for 2 hours. The solvent wasremoved under vacuum, the mixture was treated with 5 ml of toluene andthen was evaporated to dryness under vacuum. The residue was dissolvedin acetonitrile and was added to another flask containing 210 mg (3mmol) hydroxylamine hydrochloride and triethyl amine 701 μL (5 mmol) inacetonitrile at 0° C. The mixture was allowed to stir overnight. Thereaction mixture was diluted with ethyl acetate, washed with 1 N HCl(2×) and brine. The organic layer was dried over MgSO₄, filtered andstripped. The crude product was purified by flash chromatography onsilica gel eluted with hexane/ethyl acetate (20:1) to give 43 mg of3-chloro-N-(3-chloro-phenyl)-N′-hydroxy-7-pyrrolidin-1-yl-benzofuran-2-carboxamidinein 13% yield.

[0266]¹H NMR (CDCl₃) δ 7.24 (d, J=8.9Hz, 1H), 7.09 (d, J=8.1Hz, 1H),7.05 (d, J=8.0Hz, 1H), 7.00 (s, 1H), 6.89 (d, J=8.1Hz, 1H), 6.85 (s,1H), 6.66 (d, J=8.0Hz, 1H), 3.31 (s, 4H), 1.97 (s, 4H). MS (ES+): 390(M+H, 100).

Example 89

[0267]

[0268] Step 89a: To a solution of N-(3-chloro-phenyl)-N′-hydroxy-5-bromo-7-nitro-benzofuran-2-carboxamidine 2.0 g (4.9 mmol) and 1.8 mlof dihydropyran (9.8 mmol) in 10 mL of dichloromethane at roomtemperature with stirring under N₂ was added 113 mg (0.245 mmol) ofcamphorsonic acid. The resulting solution was stirred at roomtemperature for 2 h followed by addition of 34 μL of triethyl amine: Theresulting residue was diluted with ethyl acetate, washed with 1 N HCl(2×), saturate sodium bicarbonate solution and brine. The organic layerwas dried over MgSO₄, filtered and stripped. The crude product waspurified by flash chromatography on silica gel eluted with 5-10%methanol/dichloromethane to give 2.2 g of3-chloro-N-(3-chloro-phenyl)-hydroxy-5-bromo-7-nitro-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidine in 91% yield.

[0269] Step 89b: To a methanol solution ofN-(3-chloro-phenyl)-hydroxy-5-bromo-7-nitro-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidinewas added 200 mg of Pd/C. The resulted solution was stirred under 1 atmof hydrogen for 2 h. The Pd/C was filtered off through a celite pad andthe organic solution was concentrated under vacuum. The product was usedfor next reaction directly without further purification.

[0270] Step 89c: To a dichloromethane solution of 42 mg ofN-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidine was 200 μl of pyridine and 200 μl of aceticanhydride. The resulted solution was stirred at room temperature for 20min. The reaction mixture was concentrated under vacuum. The crudeproduct was purified by flash chromatography on silica gel eluted with5-10% methanol/dichloromethane to give 43 mg ofN-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamidein 99% yield.

[0271] Step 89d: To a methanol solution ofN-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamidewas added 200 mg of acidic Dowex resin. The resulted solution wasstirred at reflux temperature for 1 h. The reaction mixture was filteredand concentrated under vacuum. The crude product was purified using achromatotron and eluting with hexane/ethyl acetate (8:2) to give 25 mgN-{2-[N-(3-chloro-phenyl)-N′-hydroxy-carbamimidoyl]-benzofuran-7-yl}-acetamidein 73% yield.

[0272]¹H NMR (CD₃OD) δ 7.85 (dd, J1=2.1 Hz, J2=8.0 Hz, 2H), 7.29 (d,J=8.9 Hz, 1H), 7.21 (dd, J1=8.1 Hz, J2=2.0 Hz, 1H), 7.04 (t, J=8.0 Hz,1H), 6.93 (d, J=8.1 Hz, 1H), 6.86 (t, J=2.1 Hz, 1H), 6.67 (d, J1=8.0 Hz,J2=2.0Hz, 1H), 2.16 (s, 3H). MS (ES+): 344 (M+H, 100).

Example 90

[0273]

[0274] Following the procedures described for Example 88, substituting5-bromo-7-nitro-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide,the corresponding N-(3-chloro-phenyl)-N′-hydroxy-5-bromo-7-nitro-benzofuran-2-carboxamidine was obtained, 46 mg in 46%yield.

[0275]¹H NMR (CDCl₃) δ 8.40 (d, J=2.1 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H),7.66 (m, 1H), 7.52 (m, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.99 (s, 1H), 6.95(dm, J=8.2Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.66 (dm, J=8.0 Hz, 1H). MS(ES+): 410 (M+H, 100).

Example 91

[0276]

[0277] Following the procedures described for Example 89, substitutingmethanesulfonyl chloride for acetic anhydride in Step 89c, thecorrespondingN-(3-chloro-phenyl)-N′-hydroxy-7-methanesulfonylamino-benzofuran-2-carboxamidinewas obtained, 32 mg, 76.0% yield.

[0278]¹H NMR (CDCl₃) δ 8.11 (bs, 1H), 7.26 (m, 1H), 7.13(s, 1H), 7.07(t, J=6.9Hz, 1H), 6.98 (d, J=6.9Hz, 1H), 6.88 (t, J=1.9Hz, 1H), 6.60(dd, J1=2.1 Hz, J2=8.0 Hz, 1H), 6.65 (s, 3H). MS (ES+): 380 (M+H, 100).

Example 92

[0279]

[0280] Following the procedures described for Example 88, substituting7-piperidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidefor 7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid(3-chloro-phenyl)-amide in Example 88, theN-(3-Chloro-phenyl)-N-hydroxy-7-piperidin-1-yl-benzofuran-2-carboxamidinewas obtained, 52 mg, 28.0% yield.

[0281]¹H NMR (CDCl₃) δ 7.29 (d, J=7.4 Hz, 1H), 7.24 (m, 1H), 7.07 (m,3H), 6.98 (d, J=7.4 Hz, 1H), 6.91(t, J=1.8 Hz, 1H), 6.82 (s, 1H), 6.66(dm, J=7.3 Hz, 1H), 3.10 (m, 4H), 1.74 (m, 4H), 1.57 (m, 2H). MS (ES+):370(M+H, 100).

Example 93

[0282]

[0283] To a methanol solution of 32 mgof7N-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidinewas 200 mg of acidic Dowex resin. The resulted solution was stirred atreflux temperature for 1 h. The reaction mixture was filtered andconcentrated under vacuum. The crude product was purified using achromatotron and eluting with 5-10% methanol/dichloromethane to give 18mg of 7-amino-N-(3-chloro-phenyl)-N′-hydroxy-benzofuran-2-carboxamidinein 62% yield.

[0284]¹H NMR (CDCl₃) δ 7.98 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.46 (m,2H), 7.38 (d, J=8.0 Hz, 1H), 7.33 (m, 1H), 7.04 (t, J=8.2 Hz, 1H), 6.93(d, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.60 (dm, J=7.9 Hz, 4H). MS (ES+):302(M+H, 100).

Example 94

[0285]

[0286] Following the procedures described for Example 88, substituting7-methoxy-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,N-(3-chloro-phenyl)-N′-hydroxy-7-methoxy-benzofiiran-2-carboxamidine wasobtained 152 mg, 32% yield.

[0287]¹H NMR (CDCl₃) δ 7.16 (m, 2H), 7.04 (d, J=7.2 Hz, 1H), 6.92 (d,J=7.2 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.82 (s, 1H), 6.80 (t, J=6.2 Hz,1H), 6.68 (dm, J=7.0 Hz, 1H), 3.90 (s, 3H). MS (ES+): 317(M+H, 100).

Example 95

[0288]

[0289] Following the procedures described for Example 88, substituting5-nitro-benzofuran-2-carboxylic acid phenylamide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88 N-hydroxy-5-nitro-N′-phenyl-benzofuran-2-carboxamidine wasobtained 36 mg, 27% yield.

[0290]¹H NMR (CDCl₃) δ 8.47 (d, J=2.0 Hz, 1H), 8.23 (d, J1=7.6 Hz,J2=2.4 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.09 (d,J=7.6 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.89 (s, 1H). MS (ES+): 298(M+H,100).

Example 96

[0291]

[0292] Following the procedures described for Example 88, substituting5-nitro-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,N-(3-Chloro-phenyl)-N′-hydroxy-5-nitro-benzofuran-2-carboxamidine wasobtained 45 mg, 48% yield.

[0293]¹H NMR (CDCl₃) δ 8.48 (d, J=2.0 Hz, 1H), 8.24 (dd, J1=8.0 Hz,J2=2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.98(dm, J=7.2Hz, 1H), 6.91 (t, J=2.1 Hz, 1H), 6.89 (s, 1H), 6.89 (s, 1H),6.67 (dm, J=8.0 Hz, 1H). MS (ES+): 331 (M+H, 100).

Example 97

[0294]

[0295] Following the procedures described for Example 88, substituting5-chloro-benzofuran-2-carboxylic acid phenylamide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88 N-hydroxy-5-chloro-N′-phenyl-benzofuran-2-carboxamidinewas obtained 52 mg, 42% yield.

[0296]¹H NMR (CDCl₃) δ 7.50 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H),7.25 (dd, J1=7.6 Hz, J2=2.0 Hz, 1H), 7.21 (t, J=7.6 Hz, 2H), 7.10 (bs,1H), 7.05 (t, J=7.8 Hz, 1H), 6.87 (dm, J=8.0 Hz, 1H), 6.74 (s, 1H). MS(ES+): 287 (M+H, 100).

Example 98

[0297]

[0298] Following the procedures described for Example 88, substituting5-chloro-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,N-(3-Chloro-phenyl)-N′-hydroxy-5-chloro-benzofuran-2-carboxamidine wasobtained 64 mg, 52% yield.

[0299]¹H NMR (CDCl₃) δ 7.53 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H),7.27 (dd, J1=8.2 Hz, J2=2.4 Hz, 1H), 7.09 (t, J=8.0 Hz, 2H), 6.98 (dm,J=7.2 Hz, 1H), 6.90 (t, J=2.0 Hz, 1H), 6.83 (s, 1H), 6.67 (dm, J=7.2 Hz,1H). MS (ES+): 321 (M+H, 100).

Example 99

[0300]

[0301] Following the procedures described for Example 88, substituting5-methoxy-benzofuran-2-carboxylic acid phenylamide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88 N-hydroxy-5-methoxy-N′-phenyl-benzofuran-2-carboxamidinewas obtained 36 mg, 43% yield.

[0302]¹H NMR (CDCl₃) δ 7.30 (d, J=9.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 2H),7.03 (t, J=7.6 Hz, 1H), 6.98 (d, J=2.8 Hz, 1H), 6.91 (dd, J1=8.9 Hz,J2=2.4Hz, 1H), 6.87 (d, J=6.8 Hz, 2H), 6.78 (d, J=2.0 Hz, 1H), 3.82 (s,3H). MS (ES+): 283 (M+H, 100).

Example 100

[0303]

[0304] Following the procedures described for Example 88, substituting5-methoxy-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,N-(3-Chloro-phenyl)-N′-hydroxy-5-methoxy-benzofuran-2-carboxamidine wasobtained 51 mg, 34% yield.

[0305]¹H NMR (CDCl₃) δ 7.30 (d, J=8.9 Hz, 1H), 7.27 (bs, 1H), 7.06 (t,J=8.0 Hz, 1H), 6.98 (dm, J=7.6 Hz, 1H), 6.93 (dd, J1=9.2 Hz, J2=2.8 Hz,1H), 6.89 (t, J=2.0Hz, 2H), 6.86 (s, 1H), 6.65 (dm, J=7.6 Hz, 1H), 3.82(s, 3H). MS (ES+): 317 (M+H, 100).

Example 101

[0306]

[0307] Following the procedures described for Example 88, substituting7-ethoxy-benzofuran-2-carboxylic acid phenylamide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88, N-hydroxy-7-ethoxy-N′-phenyl-benzofuran-2-carboxamidinewas obtained 43 mg, 42% yield.

[0308]¹H NMR (CDCl₃) δ 7.19 (t, J=8.0 Hz, 2H), 7.13 (s, 1H), 7.11 (d,J=2.0 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.83 (s,1H), 6.82 (dd, J1=3.6 Hz, J2=5.6 Hz, 1H), 4.09 (q, J=6.8 Hz, 2H), 1.34(t, J=6.8 Hz, 1H). MS (ES+): 297 (M+H, 100).

Example 102

[0309]

[0310] Following the procedures described for Example 88, substituting5-ethoxy-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,N-(3-Chloro-phenyl)-N′-hydroxy-5-ethoxy-benzofuran-2-carboxamidine wasobtained (54 mg, 45% yield).

[0311]¹H NMR (CDCl₃) δ 7.15 (s, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.07 (t,J=8.0 Hz, 2H), 6.98 (dm, J=8.0 Hz, 1H), 6.92 (t, J=2.0 Hz, 1H), 6.90 (s,1H), 6.84 (dd, J1=6.0Hz, J2=2.4 Hz, 1H), 6.89 (dm, J=8.0 Hz, 1H), 4.11(q, J=6.8 Hz, 2H), 1.36 (t, J=6.8 Hz, 1H). MS (ES+): 331 (M+H, 100).

Example 103

[0312]

[0313] Following the procedures described for Example 88, substituting3-methyl-benzofuran-2-carboxylic acid phenylamide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88, N-hydroxy-3-methyl-N′-phenyl-benzofuran-2-carboxamidinewas obtained (2 mg, 57% yield).

[0314]¹H NMR (CDCl₃) δ 7.53 (d, J=7.8 Hz, 1H) 7.37 (d, J=7.6 Hz, 1H),7.31 (dt, J1=6.8 Hz, J2=1.2 Hz, 1H), 7.27 (dt, J1=7.6 Hz, J2=1.2 Hz,1H), 7.12 (t, J=8.4 Hz, 2H), 6.95 (t, J=7.2 Hz, 1H), 6.73 (d, J=7.6 Hz,2H), 2.29 (s, 3H). MS (ES+): 267 (M+H, 100).

Example 104

[0315]

[0316] Following the procedures described for Example 88, substituting3-methyl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,N-(3-Chloro-phenyl)-N′-hydroxy-3-methyl-benzofuran-2-carboxamidine wasobtained (62 mg, 54% yield).

[0317]¹H NMR (CDCl₃) δ 7.55 dm, J=8.0 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H),7.33 (t, J=7.8 Hz, 1H), 7.27 (dt, J1=7.6 Hz, J2=1.2 Hz, 1H), 7.00 (t,J=8.0 Hz, 1H), 6.92 (dm, J=8.2 Hz, 1H), 6.81 (t, J=2.0 Hz, 1H), 6.53(dm, J=7.6Hz, 1H), 2.32 (s, 3H). MS (ES+): 301 (M+H, 100).

Example 105

[0318]

[0319] Following the procedures described for Example 88, substitutingbenzofuran-2-carboxylic acid phenylamide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88 N-hydroxy-N′-phenyl-benzofuran-2-carboxamidine wasobtained (125 mg, 40% yield).

[0320]¹H NMR (CDCl₃) δ 7.55 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H),7.31 (t, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.21 (m, 1H), 7.17 (d, J=8.0 Hz,2H), 7.03 (t, J=7.2 Hz, 1H), 6.87 (m, 3H). MS (ES+): 253 (M+H, 100).

Example 106

[0321]

[0322] Following the procedures described for Example 88, substituting3-chloro-benzo[b]thiophene-2-carboxylic acid phenylamidefor7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,3-chloro-N-hydroxy-N′-phenyl-benzo[b]thiophene-2-carboxamidine wasobtained (162 mg, 62% yield).

[0323]¹H NMR (CDCl₃) δ 7.78 (m, 2H), 7.43 (m, 3H), 7.12 (t, J=7.8 Hz,2H), 6.95 (t, J=7.8 Hz, 1H), 6.81 (d, J=7.8 Hz, 2H). MS (ES+): 303 (M+H,100).

Example 107

[0324]

[0325] Following the procedures described for Example 88, substituting6-benzyloxy-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,6-Benzyloxy-N-(3-chloro-phenyl)-N′-hydroxy-benzofuran-2-carboxamidinewas obtained (51 mg, 43% yield).

[0326]¹H NMR (CDCl₃) δ 7.43 (m, 4H), 7.36 (d, J=8.4 Hz, 1H), 7.33 (tt,J1=6.8 Hz, J=1.2 Hz, 1H), 7.10 (m, 1H), 7.08 (t, J=8.0 Hz, 1H), 7.01 (m,1H), 6.98 (d, J=2.0 Hz, 1H), 6.95 (t, J=2.0 Hz, 1H), 6.92 (d, J=2.2 Hz,1H), 6.82 (s, 1H), 6.68 (dm, J=6.8 Hz, 1H), 5.07 (s, 2H). MS (ES+): 393(M+H, 100).

Example 108

[0327]

[0328] Following the procedures described for Example 88, substituting7-methoxy-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amide for7-pyrrolidin-1-yl-benzofuran-2-carboxylic acid (3-chloro-phenyl)-amidein Example 88,3-chloro-N-(3-chloro-phenyl)-N′-hydroxy-7-methoxy-benzofuran-2-carboxamidinewas obtained 1(6 mg, 15% yield).

[0329]¹H NMR (CDCl₃) δ 7.16 (m, 2H), 7.23 (m, 1H), 7.13 (d, J=8.4 Hz,1H), 7.09 (m, 1H), 7.06 (dt, J1=1.5 Hz, J2=8.0 Hz, 1H), 6.99 (d, J=5.6Hz, 1H), 6.98 (s, 1H), 6.91 (t, J=1.5 Hz, 1H), 6.74 (t, J=8.4 Hz, 1H),6.67 (dm, J=8.0 Hz, 1H), 3.86 (s, 3H). MS (ES+): 351 (M+H, 100).

Example 109

[0330]

[0331] Compound of Formula (Z): R′=3-CF₃,R″=4-(3-hydroxyimino-pyrolidin-1-yl, and R′″=Cl. Step a. A sample of thecompound from Example 52 (0.524 g, 1.31 mmol) was treated with(iPr)₃SiCl (0.364 ml, 1.7 rnmol), NEt₃ (0.293 ml, 2.1 mmol) and DMAP(0.020 g, 0.16 mmol) in DCM (6 mL) overnight at rt. The reaction mixturewas then poured into water and extracted with EtOAc. The organic layerwas separated, washed with brine, dried with anhydrous Na₂SO₄,concentrated by rotary evaporation and purified by flash chromatographyon silica gel with a gradient elution of 35-45% EtOAc/hexanes to affordthe TIPS compound as a white solid (0.34 g, 47%).

[0332] To a mixture of DMSO (0.131 mL, 1.84 mmol) and DCM (5 mL) at −78°C. under a nitrogen atmosphere was added (COCl)₂ (0.46 mL, 2.0 M in DCM)via syringe. The solution was stirred for 15 min at the low temperature.The TIPS protected compound from Step a above (0.34 g, 0.613 mmol) wasadded to the above solution. Stir continued at the low temperature foran additional hour, at which time, NEt₃ (0.388 mL, 2.79 mmol) was addedand the solution was allowed to warm to rt. It was then poured intowater and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with 20%EtOAc/hexanes as the eluent to yield the corresponding ketone as a whitesolid (0.240 g, 71%).

[0333] The above ketone (0.066 g, 0.12 mmol) was stirred withhydroxyamine hydrochloride (0.033 g, 0.47 mmol) in MeOH (1 mL) at rt.After 1 hr, the reaction was complete. It was then poured into sat.NaHCO₃ and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 70-90% EtOAc/hexanes to yield the title compound asa white solid (0.045 g, 91%). ¹H NMR (DMSO-d₆): δ 10.77 (s, 1H), 10.70(s, 1H), 8.58 (s, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H),7.28 (d, J=8.9 Hz, 1H), 7.08 (dd, J=8.1, 8.1 Hz, 1H), 6.79 (m, 2H), 6.50(d, J=8.9 Hz, 1H), 3.92 (m, 2H), 3.37 (m, 2H), 2.64 (m, 2H). MS (ES):413 [M+H]⁺.

Example 110

[0334]

[0335] Compound of Formula (Z): R′=3-CF₃,R″=4-(3-methoxyimino-pyrolidin-1-yl, and R′″=Cl. The title compound wasprepared by treating a sample of the ketone intermediate obtained inStep a of Example 200 (0.066 g, 0.12 mmol) and substituting methoxyaminehydrochloride (0.030 g, 0.36 mmol) for hydroxyamine hydrochloride inStep b. ¹H NMR (DMSO-d₆): δ 10.78 (s, 1H), 8.59 (s, 1H), 7.65 (d, J=2.1Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.08 (dd,J=8.0, 8.0 Hz, 1H), 6.80 (m, 2H), 6.50 (d, J=8.9 Hz, 1H), 3.92 (m, 2H),3.78 (s, 3H), 3.37 (m, 2H), 2.68 (m, 2H). MS (ES): 427 [M+H]⁺.

Example 111

[0336]

[0337] Compound of Formula (Z): R′=3-CF₃, R″=4-(2-hydroxyethylamino)-,and R′″=Cl. A mixture of the compound from Example 17 (0.080 g, 0.24mmol) and 2-aminoethanol (0.101 ml, 1.68 mmol) in DMSO (1 mL) was heatedto 125° C. for 24 hrs. The mixture was then cooled to rt, poured intowater and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 70-90% EtOAc/hexanes to yield the title compound asa yellowish solid (0.036 g, 40%). 1H NMR (DMSO-d₆): δ 10.54 (s, 1H),8.45 (s, 1H), 7.45 (d, J=2.1, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.08 (dd,J=7.7, 7.7 Hz, 1H), 6.80 (m, 3H), 6.52 (d, J=7.4 Hz, 1H), 5.48 (s, 1H),4.86 (t, J=6.6 Hz, 1H), 3.57 (m, 2H), 3.22 (m, 2H). MS (ES): 374 [M+H]⁺.

Example 112

[0338]

[0339] Compound of Formula (Z): R′=3-CF₃,R″=4-[2-(1-piperazino)ethylamino]-, and R′″=Cl. Following the sameprocedure as was used in Example 202 except substituting1-(2-aminoethyl)piperazine for 2-aminoethanol, the title compound wasobtained ¹H NMR (DMSO-d₆): δ 10.55 (s, 1H), 8.45 (s, 1H), 7.45 (d, J=1.9Hz, 1H), 7.39 (d, J=10.5 Hz, 1H), 7.07 (dd, J=7.2, 7.2 Hz, 1H), 6.79 (m,3H), 6.52 (d, J=8.9 Hz, 1H), 5.70 (m, 1H), 5.20 (m, 2H), 2.70 (m, 4H),2.54 (m, 2H), 2.35 (m, 4H). MS (ES): 442 [M+H]⁺.

Example 113

[0340]

[0341] Compound of Formula (Z): R′=3-CF₃,R″=4-[2-(4-hydroxyphenyl)ethylamino]-, and R′″=Cl. Following the sameprocedure as was used in Example 202 except substituting tyromine for2-aminoethanol, the title compound was obtained ¹H NMR (DMSO-d₆): δ10.53 (s, 1H), 9.16 (s, 1H), 8.46 (s, 1H), 7.45 (s, 1H), 7.39 (d, J=7.8Hz, 1H), 7.05 (m, 3H), 6.82 (m, 3H), 6.69 (m, 2H), 6.5 (d, J=7.2 Hz,1H), 5.50 (m, 1H), 3.38 (m, 2H), 2.73 (t, J=5.5 Hz, 2H). MS (ES): 450[M+H]⁺.

Example 114

[0342]

[0343] Compound of Formula (Z): R′=3-CF₃,R″=4-[2-(4-sulfomoylphenyl)ethylamino]-, and R′″=Cl. Following the sameprocedure as was used in Example 202 except substituting4-(2-aminoethyl)benzenesulfonamide for 2-aminoethanol, the titlecompound was obtained ¹H NMR (DMSO-d₆): δ 10.56 (s, 1H), 8.48 (s, 1H),7.45 (m, 2H), 7.46 (m, 3H), 7.43 (d, J=9.4 Hz, 1H), 7.30 (m, 2H), 7.10(dd, J=6.7, 6.7 Hz, 1H), 6.94 (d, J=10.0 Hz, 1H), 6.82 (m, 2H), 6.56 (d,J=8.9 Hz, 1H), 5.73 (m, 1H), 3.47 (m, 2H), 2.95 (t, J=8.3 Hz, 2H). MS(ES): 513 [M+H]⁺.

Example 115

[0344]

[0345] Step a. Methyl 4-fluro-3-trifluoromethylbenzoate (8.80 g, 39.6mmol, from Oakwood Products, Inc. West Cloumbia, S.C.) was stirred withconc. H₂SO₄ (60 mL) and fumaric HNO₃ (60 mL) overnight at rt. Themixture was then cooled with ice, poured onto ice-water and extractedwith EtOAc. The organic layer was separated, washed with brine, driedwith anhydrous Na₂SO₄, concentrated by rotary evaporation and purifiedby flash chromatography on silica gel with a gradient elution of 10-20%EtOAc/hexanes to afford a greenish oil (8.50 g, 80%).

[0346] Step b. The nitrobenzoate compound from above (8.40 g, 31.46mmol) was reduced by heating with SnCl₂.2H₂O (28.40 g, 126 mmol) inEtOAc (220 mL) at 85° C. for two hrs. After cooled to rt, it wasbasicified with sat. NaHCO₃ and extracted with EtOAc. The whole wasfiltered. The organic layer was separated, washed with brine, dried withanhydrous Na₂SO₄, concentrated by rotary evaporation and purified byflash chromatography on silica gel with a gradient elution of 30-50%EtOAc/hexanes to afford aniline as a white solid (6.58 g, 88%).

[0347] Step c. The aniline compound from Step b above (6.11 g, 25.78mmol) was added to 6N HCl (400 mL) to obtain a suspension. After cooledto −5˜−10° C., NaNO₂ (2.135 g, 30.94 mmol, dissolved in water) wasadded. After the mixture was maintained at the same temperature for 30min, NaN₃ (3.35 g, 51.56 mmol, suspended in water) was added inportions. Upon finishing addition, the mixture was warmed to rt andstayed for 1 hr at rt. It was then extracted with EtOAc. The organiclayer was separated, washed with brine, dried with anhydrous Na₂SO₄,concentrated by rotary evaporation and purified by flash chromatographyon silica gel eluting with 20% EtOAc/hexanes to afford azide as ayellowish solid (3.08 g, 45%).

[0348] Step d. The azido substituted benzoate from above (3.08 g, 11.70mmol) was hydrolyzed by treatment with LiOH.H₂O (0.983 g, 23.42 mmol) atrt for 40 min in a mixed solvent of THF (70 mL), MeOH (70 mL) and water(35 mL). It was then poured into 5% HCl and extracted with EtOAc. Theorganic layer was separated, washed with brine, dried with anhydrousNa₂SO₄, concentrated by rotary evaporation and purified by flashchromatography on silica gel eluting with a gradient elution of 0-10%MeOH/EtOAc to afford acid as a greenish solid (2.90 g, 99%). Thematerial contained a 12% minor product arising from the methoxysubstitution of the fluorine atom. The latter was readily separated inthe following steps.

[0349] Step e. The acid from above (1.150 g, 5 mmol) was then treatedwith (COCl)₂ (5.0 mL, 2.0 M/DCM) in DCM (30 mL) in the presence of 3drops of DMF as catalyst for 2 hrs or until bubbles ceased. The solventwas then removed. The acyl chloride thus obtained (in DCM) was added toanother flask at 0° C. containing 3-chloroaniline (0.582 mL, 5.5 mmol),TEA (2.10 mL, 15 mmol) in DCM (50 mL). The mixture was warmed to rt andstirred for 1 hr at rt. It was then poured into water and extracted withEtOAc. The organic layer was separated, washed with brine, dried withanhydrous Na₂SO₄, concentrated by rotary evaporation and purified byflash chromatography on silica gel with a gradient elution of 10-30%EtOAc/hexanes to afford amide as a white solid (0.220 g, 13%, notoptimized).

[0350] Step f. Amide from above (0.220 g, 0.61 mmol) was then heatedwith PCl₅ (0.192 g, 0.92 mmol) in 6 ml of 1,2-dichloroethane to 70° C.in a sealed flask for 5 hrs. It was then cooled to rt and the solventremoved. The residue was stirred with NH₂OH.HCl (0.127 g, 1.83 mmol) andTEA (0.51 mL, 3.66 mmol) in acetonitrile (4 mL) for 4 hrs at rt. It wasthen poured into 5% HCl and extracted with EtOAc. The organic layer wasseparated, washed with brine, dried with anhydrous Na₂SO₄, concentratedby rotary evaporation and purified by flash chromatography on silica gelwith a gradient elution of 20-35% EtOAc/hexanes to afford the titlecompound as a yellowish solid (0.090 g, 39%).

[0351]¹H NMR (DMSO-d₆): δ 11.08 (s, 1H), 8.76 (s, 1H), 7.58 (d, J=7.9Hz, 1H), 7.42 (d, J=6.0 Hz, 1H), 7.10 (dd, J=8.0, 8.0 Hz, 1H), 6.85 (m,2H), 6.51 (d, J=9.7 Hz, 1H). MS (ES): 372 [M−H]⁺.

Example 116

[0352]

[0353] A sample of the compound from Example 115 (0.300 g, 0.8 mmol) inTHF (1 mL) and EtOH (6 mL) at 0° C. was added a premixed solution ofSnCl₂.2H₂O (0.271 g, 1.2 mmol) and 4.33 mL of 2M NaOH at 0° C. slowly.After 10 min, the mixture was filtered. The filtrate was collected,poured into water and extracted with EtOAc. The organic layer wasseparated, washed with brine, dried with anhydrous Na₂SO₄, concentratedby rotary evaporation and purified by flash chromatography on silica gelwith a gradient elution of 50-80% EtOAc/hexanes to afford the titlecompound as an wax (0.208 g, 75%). ¹H NMR (DMSO-d₆): δ 10.82 (s, 1H),8.58 (s, 1H), 7.09 (m, 2H), 6.80 (m, 3H), 6.48 (d, J=7.8 Hz, 1H), 5.75(s, 2H). MS (ES): 348 [M+H]⁺.

Example 117

[0354]

[0355] Step a. 4-Chloro-5-nitro-3-trifluoromethylbenzoic acid (5.03 g,18.7 mmol, prepared from the nitration of4-chloro-3-trifluoromethylbenzoic acid under the conditions described inStep a of Example 115) was treated with (COCl)₂ (18.7 mL, 2.0 M/DCM) inDCM (100 mL) in the presence of 2 drops of DMF as catalyst for 2.5 hrs.The solvent was then removed. The obtained acyl chloride (in DCM) wasadded to another flask at 0° C. containing 3-chloroaniline (1.95 ml,18.7 mmol), TEA (7.82 mL, 56.1 mmol) in DCM (200 mL). The mixture wasthen warmed to rt and stayed for 1 hr at rt. It was then poured intowater and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 20-30% EtOAc/hexanes to afford amide as a yellowishsolid (6.80 g, 96%).

[0356] Step b. A sample of the amide from above (0.050 g, 0.132 mmol)was also heated with pyrrolidine (1.30 g, 3.43 mmol) in DMSO (15 mL) for2 hrs at 50° C. It was then cooled to rt, poured into water andextracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel eluting with 20%EtOAc/hexanes to afford the pyrrolino-substituted compound as a brightyellow solid (1.28 g, 90%).

[0357] Step c. A sample of this compound (1.28 g, 3.37 mmol), SnCl₂.2H₂O(3.04 g, 13.47 mmol) and EtOAc (80 mL) was heated to 80° C. in a sealedflask for 40 min. It was then cooled to rt, basified with sat. NaHCO₃and extracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel with a gradientelution of 30-50% EtOAc/hexanes to afford an aniline as a yellow solid(0.375 g, 29%).

[0358] Step d. A mixture of the aniline from above (0.030 g, 0.078mmol), 3,4-dichlorophenylisocyanate (0.060 g, 0.32 mmol) in DCM (1.5 mL)was heated in a sealed vial to 70° C. for 1 hr. It was then cooled tort, quenched with MeOH, poured into water and extracted with EtOAc. Theorganic layer was separated, washed with brine, dried with anhydrousNa₂SO₄, concentrated by rotary evaporation and purified by flashchromatography on silica gel with a gradient elution of 30-50%EtOAc/hexanes to afford the urea compound as a white solid (0.030 g,67%). ¹H NMR (DMSO-d₆): δ 10.53 (s, 1H), 9.83 (s, 1H), 8.76 (d, J=1.8Hz, 1H), 8.15 (s, 1H), 7.94 (m, 3H), 7.70 (d, J=11.1 Hz, 1H), 7.55 (d,J=8.8 Hz, 1H), 7.38 (m, 2H), 7.18 (d, J=8.9 Hz, 1H), 3.15 (m, 4H), 2.03(m, 4H). MS (ES): 571 [M+H]⁺.

Example 118

[0359]

[0360] To a solution of 3,5-diaminobenzotrifluoride (2.114 g, 12 mmol)in DCM (30 mL) at 0° C. was added 4-chloro-3-(trifluoromethyl)phenylisocyanate (2.659 g, 12 mmol in DCM) dropwise. The mixture was warmed tort and stirred for 1 hr at rt. It was then quenched with MeOH, pouredinto water and extracted with EtOAc. The organic layer was separated,washed with brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 10-30% CH₃CN/DCM to afford 118 as a white solid(4.10 g, 86%). ¹H NMR (DMSO-d⁶): δ 9.09 (s, 1H), 8.88 (s, 1H), 8.12 (s,1H), 7.61 (m, 2H), 7.00 (s, 1H), 6.88 (s, 1H), 6.50 (s, 1H), 5.58 (s,2H). MS (ES): 398 [M+H]⁺.

Example 119

[0361]

[0362] To a solution amino urea compound from Example 118 (0.100 g, 0.25mmol), TEA (0.140 ml, 1 mmol) in DCM (1.5 ml) at 0° C. was added allylchloroformate (0.120 ml, 1 mmol). The mixture was warmed to rt andstayed for 2 hr at rt. It was poured into water and extracted withEtOAc. The organic layer was separated, washed with brine, dried withanhydrous Na₂SO₄, concentrated by rotary evaporation and purified byflash chromatography on silica gel with a gradient elution of 30-60%EtOAc/hexanes to give the title compound as a white solid (0.015 g,12%). ¹H NMR (DMSO-d₆): δ 10.08 (s, 1H), 9.26 (s, 1H), 9.15 (s, 1H),8.11 (d, J=2.1 Hz, 1H), 7.76 (s, 1H), 7.63 (m , 3H), 7.50 (s, 1H), 5.98(m, 1H), 5.37 (d, J=17.8 Hz, 1H), 5.26 (d, J=11.1 Hz, 1H), 4.62 (m, 2H).MS (ES): 480 [M−H]⁺.

Example 120

[0363]

[0364] The title compound was synthesized by treating a sample of thecompound from Example 118 with phenylthioacetyl chloride in the presenceof triethylamine in DCM at 0° C. for 2 hr. ¹H NMR (DMSO-d₆): δ 10.54 (s,1H), 9.30 (s, 1H), 9.19 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.95 (s, 1H),7.63 (m, 4H), 7.42 (m, 2H), 7.33 (m, 2H), 7.20 (dd, J=6.7, 6.7 Hz, 1H),3.88 (s, 2H). MS (ES): 546 [M−H]⁺.

Example 121

[0365]

[0366] The title compound was synthesized following conditions forExample 120 except substituting 4-chlorophenoxyacetyl chloride forphenylthioacetyl chloride. ¹H NMR (DMSO-d₆): δ 10.43 (s, 1H), 9.30 (s,1H), 9.19 (s, 1H), 8.13 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.71 (s, 1H),7.63 (m, 3H), 7.36 (m, 2H), 7.03 (m, 2H), 4.74 (s, 2H). MS (ES): 564[M−H]⁺.

Example 122

[0367]

[0368] The title compound was synthesized from the treatment of a sampleof compound from Example 118 with 4-trifluoromethylbenzenesulfonyl andtriethylamine in DCM. ¹H NMR (DMSO-d₆): δ 10.93 (s, 1H), 9.33 (s, 1H),9.19 (s, 1H), 8.08 (s, 1H), 8.00 (m, 4H), 7.63 (m, 3H), 7.52 (s, 1H),6.99 (s, 1H). MS (ES): 604 [M−H]^('.)

Example 123

[0369]

[0370] The title compound was synthesized in 4 steps according to thefollowing sequence.

[0371] Step a. A mixture of 1-fluoro-3-iodo-5-nitrobenzene (2.733 g,10.24 mmol), FSO₂CF₂CO₂Me (3.26 mL, 25.6 mmol), CuI (2.342 g, 12.3 mmol)in DMF (30 mL) was heated to 90° C. for 2 days under an nitrogenatmosphere. It was then poured into water and extracted with EtOAc. Theorganic layer was separated, washed with brine, dried with anhydrousNa₂SO₄, concentrated by rotary evaporation and purified by flashchromatography on silica gel with a gradient elution of 10-30%EtOAc/hexanes to yield 3-fluoro-5-nitrobenzotrifluoride.-as an oil (1.76g, 82%).

[0372] Step b. A mixture of 3-fluoro-5-nitrobenzotrifluoride (0.120 g,0.57 mmol), pyrrolidine (0.200 mL, 2.4 mmol) and DMSO (1.2 mL) wasstirred for 1 hr. It was then poured into water and extracted withEtOAc. The organic layer was separated, washed with brine, dried withanhydrous Na₂SO₄, concentrated by rotary evaporation and purified byflash chromatography on silica gel with a gradient elution of 20-30%EtOAc/hexanes to yield the pyrrolino substituted product as a brightyellow solid (0.085 g, 57%).

[0373] Step c. The above intermediate (0.083 g, 0.32 mmol) was heatedwith SnCl₂.2H₂O (0.287 g, 1.27 mmol) in EtOAc (3 mL) to 80° C. in asealed vial for 1 hr. It was then cooled to rt, basified with sat.NaHCO₃ and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 30-60% EtOAc/hexanes to afford the correspondingamine as an oil (0.055 g, 72%).

[0374] Step d. The obtained aniline above (0.055 g, 0.23 mmol) wasstirred with 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.111 g, 0.5mmol) in DCM (1.5 mL) at rt for 10 min. It was then poured into waterand extracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel with a gradientelution of 0-40% EtOAc/DCM to yield the title compound as a white solid(0.090 g, 87%). ¹H NMR (DMSO-d₆): δ 9.15 (s, 1 H), 9.00 (s, 1H), 8.09(s, 1H), 7.62 (m, 2H), 7.10 (s, 1H), 6.80 (s, 1H), 6.40 (s, 1H), 3.24(m, 4H), 1.96 (m, 4H). MS (ES): 452 [M+H]⁺.

Example 124

[0375]

[0376] The title compound was synthesized according to the same sequenceas was used for Example 123 except replacing pyrrolidine with2-methoxymethylpyrrolidine in Step b. ¹H NMR (DMSO-d₆): δ 9.15 (s, 1H),9.02 (s, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.63 (m, 2H), 7.20 (s, 1H), 6.86(s, 1H), 6.48 (s, 1H), 3.86 (m, 1H), 3.20 ˜3.40 (m, 3H), 3.29 (s, 3H),3.09 (m, 1H), 1.94 (m, 4H). MS (ES): 496 [M+H]⁺.

Example 125

[0377]

[0378] The title compound was synthesized according to the same sequenceas was used for Example 123 with slightly modified conditions startingwith 3-fluoro-5-nitrobenzotrifluoride and morpholine in Step b. ¹H NMR(DMSO-d₆): δ 9.24 (s, 1H), 9.05 (s, 1H), 8.09 (d, J=2.5 Hz, 1H), 7.62(m, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 6.86 (s, 1H), 3.74 (m, 4H), 3.16(m, 4H). MS (ES): 468 [M+H]⁺.

Example 126

[0379]

[0380] The title compound was synthesized following a similar sequenceof reactions as described in Example 123.

[0381] Step a. A sample of 3-fluoro-5-nitrobenzotrifluoride (0.209 g, 1mmol), 2-aminoethanol (0.244 g, 4 mmol) and DMSO (3.5 mL) was stirredfor 20 hrs at 70° C. It was then cooled to rt, poured into brine andextracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel eluting with 80%EtOAc/hexanes to yield the 2-hydroxyethylamino substituted product as abright yellow solid (0.222 g, 89%).

[0382] Step b. This intermediate (0.075 g, 0.3 mmol) was heated withtriphosgene (0.300 g, 1 mmol) in DCM (2 mL) to 80° C. in a sealed vialfor 2 hrs. It was then cooled to rt, poured into water and extractedwith EtOAc. The organic layer was separated, washed with brine, driedwith anhydrous Na₂SO₄, concentrated by rotary evaporation and purifiedby flash chromatography on silica gel with a gradient elution of 30-70%EtOAc/hexanes to afford the corresponding oxolidinone as a white solid(0.036 g, 43%).

[0383] Step c. The above intermediate (0.031 g, 0.112 mmol) was heatedwith SnCl₂.2H₂O (0.101 g, 0.45 mmol) in EtOAc (3 ml) to 80° C. in asealed vial for 1 hr. It was then cooled to rt, basified with sat.NaHCO₃ and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 60-90% EtOAc/hexanes to afford the correspondinganiline.

[0384] Step d. The aniline obtained above (0.011 g, 0.04 mmol) wasstirred with 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.040 g,0.18 mmol) in DCM (2 ml) and DMF (0.5 ml) at rt for 30 min. It waspoured into water and extracted with EtOAc. The organic layer wasseparated, washed with brine, dried with anhydrous Na₂SO₄, concentratedby rotary evaporation and purified by flash chromatography on silica gelwith a gradient elution of 70-100% EtOAc/hexanes to afford the titlecompound as white solid (0.011 g, 59%). ¹H NMR (DMSO-d₆): δ 9.39 (s,1H), 9.24 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.63 (m,2H), 7.53 (s, 1H), 4.46 (t, J8.3 Hz, 2H), 4.10 (t, J=8.3 Hz, 2H). MS(ES): 466 [M−H]⁺.

Example 127

[0385]

[0386] The title compound was synthesized according to the same sequenceas was used in Example 126 with slightly modified conditionssubstituting ethylenediamine for 2-aminoethanol in Step a in an overallyield of 37%. ¹H NMR (DMSO-d₆): δ 9.25 (s, 1H), 9.15 (s, 1H), 8.09 (d,J=2.3 Hz, 1H), 7.78 (s, 1H), 7.60 (s, 4H), 7.19 (s, 1H), 3.88 (t, J=8.3Hz, 2H), 3.42 (t, J=8.3 Hz, 2H). MS (ES): 465 [M−H]⁺.

Example 128

[0387]

[0388] A mixture of 3-methoxy-5-trifluoromethylaniline (0.077 g, 0.4mmol, available from Oakwood),N-(4-chloro-3-trifluoromethylphenyl)glycine (0.051 g, 0.2 mmol), EDC(0.153 g, 0.8 mmol), HOBt (0.109 g, 0.8 mmol) in DMF (2.5 mL) wasstirred at rt overnight. It was then poured into sat. NaHCO₃ andextracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel with a gradientelution of 30-60% EtOAc/hexanes to afford the title compound as a whitesolid (0.035 g, 41%). ¹H NMR (DMSO-d₆): δ 10.36 (s, 1H), 7.61 (s, 1H),7.47 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 6.94 (s,1H), 6.81 (d, J=8.8 Hz, 1H), 6.70 (s, 1H), 3.98 (s, 2H), 3.80 (s, 3H).MS (ES): 425 [M−H]⁺.

[0389] The required N-(4-chloro-3-trifluoromethylphenyl)glycine wasprepared as follows. A mixture of 4-chloro-3-trifluoromethylaniline(1.369 g, 7 mmol), ethyl bromoacetate (1.55 mL, 14 mmol), K₂CO₃ (2.764g, 20 mmol) in DMF (40 mL) was heated at 70° C. overnight. It was thenpoured into water and extracted with EtOAc. The organic layer wasseparated, washed with brine, dried with anhydrous Na₂SO₄, concentratedby rotary evaporation and purified by flash chromatography on silica gelwith a gradient elution of 20-40% EtOAc/hexanes to afford ethylN-(4-chloro-3-trifluoromethylphenyl)glycine as a white solid (0.180 g,9%).

[0390] The glycine ester (0.180 g, 0.64 mmol) was stirred with LiOH.H₂O(0.054 g, 1.28 mmol) in a mixed solvent of THF (2 mL), MeOH (2 mL) andwater (1 ml) for 30 min. The mixture was then adjusted to pH=6 withHOAc. It was then poured into water and extracted with EtOAc. Theorganic layer was separated, washed with brine, dried with anhydrousNa₂SO₄, concentrated by rotary evaporation and purified by flashchromatography on silica gel with a gradient elution of 0-100%MeOH/EtOAc to afford N-(4-chloro-3-trifluoromethylphenyl)glycine as afoam solid (0.160 g, 98%).

Example 129

[0391]

[0392] A mixture of3-(2-methoxymethylpyrrolidino)-5-trifluoromethylaniline (0.083 g, 0.3mmol, obtained as an intermediate for the preparation of the compound inExample 124, N-(4-chloro-3-trifluoromethylphenyl)glycine (0.051 g, 0.2mmol), EDC (0.115 g, 0.6 mmol), HOBt (0.082 g, 0.6 mmol) in DMF (2 ml)was stirred at rt overnight. It was then poured into sat. NaHCO₃ andextracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel with a gradientelution of 30-60% EtOAc/hexanes to give the title compound as a whitesolid (0.055 g, 55%). ¹H NMR (DMSO-d₆): δ 10.18 (s, 1H), 7.37 (d, J=7.8Hz, 1H), 7.29 (s, 1H), 7.10 (s, 1H), 7.03 (s, 1H), 6.80 (m, 1H), 6.68(m, 1H), 6.52 (s, 1H), 3.95 (s, 2H), 3.83 (m, 1H), 3.30 (m, 1H), 3.27(s, 3H), 3.07 (m, 1H), 1.93 (m, 4H). MS (ES): 510 [M+H]⁺.

Example 130

[0393]

[0394] This compound was prepared in two steps. To a solution of3,5-diaminobenzotrifluoride (0.705 g, 4 mmol) in DCM (20 ml) at 0° C.was added 4-chlorophenoxy acetyl chloride (0.624 ml, 4 mmol). Themixture was warmed to rt and stirred for 1 hr at rt. It was then pouredinto water and extracted with EtOAc. The organic layer was separated,washed with brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 30-70% EtOAc/hexanes to mono acylated compound as anoff-white solid (0.420 g, 30%).

[0395] The mono aniline from above (0.138 g, 0.4 mmol),N-(4-chloro-3-trifluoromethylphenyl)glycine (0.051 g, 0.2 mmol), EDC(0.153 g, 0.8 mmol), HOBt (0.109 g, 0.8 mmol) in DMF (2.5 ml) wasstirred at rt overnight. It was then poured into sat. NaHCO₃ andextracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel with a gradientelution of 40-70% EtOAc/hexanes to give the title compound as anoff-white solid (0.046 g, 39%). ¹H NMR (DMSO-d₆): δ 10.44 (m, 2H), 8.19(s, 1H), 7.76 (m, 2H), 7.36 (m, 3H), 7.02 (m, 3H), 6.82 (d, J=10.0 Hz,1H), 6.70 (m, 1H), 4.73 (s, 2H), 3.98 (d, J=5.9 Hz, 2H). MS (ES): 580[M+H]⁺.

Example 131

[0396]

[0397] The title compound was prepared according the reaction sequencedescribed below.

[0398] Step a. A mixture of 3-fluoro-5-nitrobenzotrifluoride (0.125 g,0.6 mmol), ethylenediamine (0.180 ml, 2.4 mmol) was heated to 70° C.overnight. The mixture was then cooled to rt, poured into water andextracted with EtOAc. The organic layer was separated, washed withbrine, dried with anhydrous Na₂SO₄, concentrated by rotary evaporationand purified by flash chromatography on silica gel with a gradientelution of 0-15% NH₄OH in 30 MeOH/DCM to the N-(2-aminoethyl)aniline asa white solid (0.103 g, 41%).

[0399] Step b. A mixture of the aniline from above (0.050 g, 0.2 mmol),2,5,6-trichlorobenzimidazole (0.050 g, 0.226 mmol),diisopropylethylamine (0.1 mL, 0.57 mmol) in DMSO (1 mL) was heated to150° C. for 1.5 hrs. The mixture was then cooled to rt, poured intowater and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 0-20% MeOH/EtOAc to yield the coupled compound as ayellow oil (0.028 g, 32%).

[0400] Step c. The product from above (0.027 mg, 0.062 mmol) was thenheated with SnCl₂.2H₂O (0.070 g, 0.3 mmol) in EtOAc (1 ml) to 80° C. ina sealed vial for 30 min. It was then cooled to rt, basified with sat.NaHCO₃ and extracted with EtOAc. The organic layer was separated, washedwith brine, dried with anhydrous Na₂SO₄, concentrated by rotaryevaporation and purified by flash chromatography on silica gel with agradient elution of 0-30% MeOH/EtOAc to give the aniline as a brownishsolid (0.020 g, 80%).

[0401] Step d. To a solution of the aniline form above (0.020 g, 0.05mmol), TEA (0.030 ml, 0.21 mmol) in DCM (1 mL) at rt was added4-chlorophenoxyacetyl chloride (0.015 mL, 0.1 mmol). After stirred for10 min, it was poured into water and extracted with EtOAc. The organiclayer was separated, washed with brine, dried with anhydrous Na₂SO₄,concentrated by rotary evaporation and purified preparative TLC using 5%MeOH/DCM as the developing solvent to yield the desired product as asolid (2 mg, 6.8%). ¹H NMR (DMSO-d₆): δ 11.06 (s, 1H), 10.11 (s, 1H),7.33 (m, 4H), 7.18 (m 2H), 7.01 (m, 3H), 6.70 (s, 1H), 6.38 (m, 1H),4.70 (s, 2H), 3.46 (m, 2H), 3.28 (m, 2H). MS (ES): 572 [M+H]⁺.

Example 1321-(4-Chloro-3-trifluoromethyl-phenyl)-3-(3-methoxymethoxy-5-trifluoromethyl-phenyl)-urea(132)

[0402] Step a. Methoxymethyl chloride (1.6 mL, 20.9 mmol) was added to adichloromethane (50 mL) solution containing3-nitro-5-trifluoraomethylphenol (2.89 g, 13.9 mmol) anddiisopropylethylamine (4.8 mL, 27.8 mmol). After 3 hours of stirring atroom temperature, the solution was washed with water (100 mL), brine (50mL), dried over Na₂SO₄, and concentrated. The resulting oil was thenhydrogenated over 10% Pd/C (300 mg) in ethanol (70 mL) at atmosphericpressure for 3 h. The suspension was filtered though a cake of celiteand concentrated to give 3-Methoxymethoxy-5-trifluoromethyl-phenylamineas a light yellow oil.

[0403] Step b. 3-Methoxymethoxy-5-trifluoromethyl-phenylamine (237 mg,1.07 mmol) and 4-choloro-3-trifluoromethylphenyl isocyanate (238 mg,1.07 mmol) were dissolved in acetonitrile (20 mL) and heated at refluxfor 6 hours. The solvent was then removed using reduced pressure and theresulting solid was purified using silica gel flash chromatographyeluting with a solution of 20% EtOAc/hexanes . Similar fractions werepooled and concentrated to give the urea product (0.421 g, 89%) as anoff-white solid.

[0404]¹H NMR (CD₃OD) δ 7.80 (d, J=2 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.50(d, J=8 Hz, 1 H), 7.45 (s, 1H), 7.43 (s, 1H), 6.96 (s, 1H), 5.31 (s,2H), 3.50 (s, 3H); Electrospray MS (MH+) m/z 443.

Example 1331-(4-Chloro-3-trifluoromethyl-phenyl)-3-(3-hydroxy-5-trifluoromethyl-phenyl)-urea(133)

[0405]1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(3-methoxymethoxy-5-trifluoromethyl-phenyl)-urea(100 mg, 0.25 mmol) from above was dissolved in a 1:1 solution of 3NHCl/ethyl acetate (20 mL) and stirred vigorously at room temperature for16 h. Additional ethyl acetate was then added (50 mL) and the mixturewas washed with water (2×50 mL), brine (50 mL), dried over Na₂SO₄, andconcentrated. The resulting residue was purified using silica gel flashchromatography eluting with a 3:1 hexane/ethyl acetate solution. Similarfractions were pooled and concentrated to the title compound (72 mg,72%) as an off-white solid. ¹H NMR (CD₃OD) δ 7.97 (d, J=2 Hz, 1H), 7.64(dd, J=2 Hz, J=8 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.22(s, 1H), 7.21 (s,1H), 6.75 (s, 1H); Electrospray MS (MH+) m/z 399.

Example 1341-(4-chloro-3-trifluoromethyl-phenyl)-3-(3-allyl-5-trifluoromethyl-phenyl)-urea(134)

[0406] The phenol compound obtained from Example 133 was treated withallyl bromide (1 eq.), and K₂CO₃ (2 eq.) in DMF at 60° C. for 24 h.After the reaction was finished, the resulting solution was directlyinjected on a preparative reverse phase HPLC column and fractions, whichcontained the desired product mass, were collected and concentratedusing the Genevac system. ¹H NMR (CD₃OD) δ 7.98 (d, J=2 Hz, 1H), 7.65(dd, J=2 Hz, J=8 Hz, 1H) 7.50 (d, J=8 Hz, 1H), 7.38 (s, 1H), 7.34 (s,1H), 6.86 (s, 1H), 6.07 (m, 1H), 5.42 (dq, J=2 Hz, J=17 Hz, 1H), 5.29(dq, J=2 Hz, J=12 Hz, 1H), 4.61 (dt, J=2 Hz, J=5 Hz, 2H).

Example 1351-(4-chloro-3-trifluoromethyl-phenyl)-3-(3-(3-chlorobenzyl)-5-trifluoromethyl-phenyl)-urea(135)

[0407] The title compound was synthesized following the same proceduredescribed in Example 134. ¹H NMR (CD₃OD) δ 7.99 (d, J=2 Hz, 1H), 7.65(dd, J=2 Hz, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.46 (m, 2H), 7.40 (m,2H), 7.32 (s, 1H), 6.93 (s, 1H), 5.14 (s, 2H).

Example 136N-[3-(3-Chloro-phenoxymethyl)-5-trifluoromethyl-phenyl]-2-(4-piperidin-1-yl-3-trifluoromethyl-phenylamino)-acetamide(136)

[0408] Step a. Preparation of4-Piperidin-1-yl-3-trifluoromethyl-phenylamine: Piperidine (1.7 mL, 17.2mmol) and 2-fluoro-5-nitrobenzotrifluoride (3 g, 14.3 mmol, availableAldrich Chemical) were dissolved in DMF (25 mL) and heated to 110° C. ina sealed tube for 24 h. The reaction was then cooled to room temperaturediluted with ethyl acetate (100 mL) and washed with water (2×150 mL),brine (50 mL), dried over N₂SO₄, and concentrated to give a yelloworange oil; Electrospray MS (MH⁺), m/z 275. The oil was thenhydrogenated over 10% Pd/C (300 mg) in ethanol (50 mL) at atmosphericpressure for 24 h. The suspension was then filtered though a cake ofcelite and concentrated to give the corresponding aniline (3.50 g, 100%)as a light yellow oil. This material was used in the next step withoutfurther purification.

[0409] Step b. α-Bromoacetyl bromide (11.6 μL, 0.13 mmol) was added to adichloromethane solution (2 μL) containing3-(3-chlorophenyl)-5-trifluoromethylaniline (40 mg, 0.13 mmol) andtriethylamine (18 μL, 0.13 mmol) at room temperature. After stirringovernight, excess solvent was removed, DMF (2 mL) and the4-piperidin-1-yl-3-trifluoromethylaniline obtained above were added, andthe entire mixture was heated at 70° C. for 8 h. The resulting solutionwas directly injected on a preparative reverse phase HPLC column andfractions, which contained the desired product mass, were collected andconcentrated. ¹H NMR (CD₃OD) δ 8.00 (s, 1H), 7.88 (s, 1H), 7.52 (s, 1H),7.42 (d, J=8 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.04 (t, J=2 Hz, 1H),6.89-6.98 (m, 3H), 6.88 (dd, J=2 Hz, J=8 Hz, 1H), 5.14 (s, 2H), 4.00 (s,2H), 3.02 (m, 4H), 1.77 (m, 4H), 1.61 (m, 2H); Electrospray MS (MH+) m/z586.

Example 137

[0410] Compound 137. Step a. Methyl 3-amino-5-trifluoromethylbenzozate(2.0 g, 9.13 mmol, obtained from the esterification of the commerciallyavailable 3-nitro-5-trifluoromethylbenzoic acid followed by reduction ofthe nitro group over Pd/C under atmospheric hydrogen) and2,5-dimethoxytetrahydrofuran (5.91 g, 45.7 mmol) in acetic acid (15 mL)were heated at 60° C. for 1.5 hrs. After cooled to rt, the reactionmixture was diluted with ethyl acetate and washed with saturated NaHCO₃and brine. The organic layer was dried with Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatography onsilica gel eluted with 4:1 to 3:1 hexanes/AcOEt. This product was thenfurther purified by recrystallization from ether/hexanes to give pyrroleproduct (1.71 g, 69.6%). ¹H (CDCl₃) δ 8.25 (s, 1H), 8.12 (s, 1H), 7.80(s, 1H), 7.16 (d, J=6.0 Hz, 1H), 6.40 (d, J=6.0 Hz, 1H), 3.97 (s, 3H).

[0411] Step b. A portion of the pyrrole from Step a (0.766 g, 285 mmol)was treated with LAH (1 M solution in THF, 8.6 mL) in THF (15 mL) at 0°C. After standard work-up, the corresponding alcohol was obtained (0.707g, 87.0%)

[0412] Step c. A sample of the alcohol form Step b (57 mg, 0.224 mmol)and 4-chloro-3-3trifluoromethylphenyl isocyanate (55 mg, 0.248 mmol)were stirred at rt in DCM. At the completion of the reaction, whichtypically takes overnight stirring, the reaction mixture was dilutedwith DCM and washed with NaHCO₃. The organic layer was dried over MgSO₄,filtered and concentrated. The crude product was purified bychromatography on Silica gel eluted with 4:1 hexanes/EtOAc to give thedesired product (71 mg, 69.3%). ¹H NMR (DMSO) δ 10.3 (s, 1H) 8.01 (s,1+1H), 7.91 (s, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.65 (s, 1H), 7.62 (d,J=7.0 Hz, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 6.31 (d, J=6.0 Hz, 2H), 5.30(d, J=6.0 Hz, 2H), 2.5 (s, 2H).

Example 138

[0413] Compound 138. Step a. A sample of the alcohol compound from Stepb of Example 137 above was converted to the benzylamine in a three-stepoperation, activation of the alcohol to its mesylate, displacement ofthe mesylate by azide, and reduction of the azide to amine.

[0414] Step b. A sample of the amine from Step a above was treated withand 4-chloro-3-trifluoromethylphenyl isocyanate following the sameconditions described to give the title compound. ¹H NMR (DMSO) δ 9.20(s, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.62 (d, J=7.0 Hz,1H), 7.55 (d, J=7.0 Hz, 1H), 7.50 (d, J=5.0 Hz, 2H), 7.50 (s, 1H), 7.00(t, J=2.5 Hz, 1H), 6.30 (d, J=5.0 Hz, 2H), 4.40 (d, J=2.5 Hz, 2H).

Example 139

[0415]

(4-Chloro-3-trifluoromethyl-phenyl)-carbamic acid3-(2-phenylsulfanyl-acetylamino)-5-trifluoromethyl benzyl ester (139)

[0416] Step 1a. To a THF/ethanol(10:1) solution of3-(2-Phenylsulfanyl-acetylamino)-5-trifluoromethyl-benzoic acid methylester (252 mg, 0.68 mmol) was added sodium borohydride (46 mg, 1.4mmol), and the mixture was stirred at 65° C. for 2 hours. The reactionmixture was left overnight. The mixture was diluted with ethyl acetate,washed with 1 N HCl (2×) and brine. The organic layer was dried overMgSO₄, filtered and stripped. The crude product was purified by flashchromatography on silica gel eluted with hexane/ethyl acetate (4:1) togive 126 mg ofN-(3-Hydroxymethyl-5-trifluoromethyl-phenyl)-2-phenylsulfanyl-acetamidein 54% yield.

[0417] Step 1b. To a CH₂Cl₂ solution ofN-(3-Hydroxymethyl-5-trifluoromethyl-phenyl)-2-phenylsulfanyl-acetamide(126 mg, 0.37mmol) was added1-Chloro-4-isocyanato-2-trifluoromethyl-benzene (86 mg, 0.38 mmol), andthe mixture was stirred at room temperature for 2 hours. The organicsolvent was removed under vacuum and the crude product was purified byflash chromatography on silica gel eluted with hexane/ethyl acetate(3:1) to give 170.9 mg of (4-Chloro-3-trifluoromethyl-phenyl)-carbamicacid 3-(2-phenylsulfanyl-acetylamino)-5-trifluoromethyl benzyl ester in82% yield. ¹H NMR (CDCl₃): δ 3.80(s, 3H), 5.19(s, 2H), 7.05(bs, 1H),7.24-7.28(m, 2H), 7.31(d, J=10 Hz, 1H), 7.35(m, 5H), 7.42(d, J=9.6 Hz,1H), 7.50(dd, J=9.6, 2 Hz, 1H), 7.54(m, 2H), 7.64(s, 1H), 7.74(d, J=2Hz, 1H), 7.82(s, 1H), 8.75(s, 1H). MS SEI m/z relative intensity: M+H,563.2(100)

Example 140

[0418]

2-(3-Chloro-phenylamino)-N-{3-[2-(3-chloro-phenylamino)-acetylamino]-5-trifluoromethyl-phenyl}acetamide(140)

[0419] To a CH₂Cl₂ solution of2-Bromo-N-[3-(2-bromo-acetylamino)-5-trifluoromethyl-phenyl]-acetamide(150 mg, 0.30 mmol) at room temperature was added 3-chloroaniline (100μL), the mixture was stirred at room temperature for 1 hour. The mixturewas diluted with ethyl acetate, washed with NaHCO₃ solution followed bylN HCl (2×) and brine. The organic layer was dried over MgSO₄, filteredand stripped and the crude product was purified by flash chromatographyon silica gel eluted with hexane/ethyl acetate (2:1) to give 132 mg ofthe title compound in 92% yield. ¹H NMR (400 MHz, CDCl₃): δ 3.87(s, 4H),6.49(dd, J=2, 8.4 Hz, 2H), 6.63(s, 2H), 6.79(d, J=2, 8.4 Hz, 2H),7.10(t, J=8.0 Hz, 2H), 7.46(s, 2H), 8.20(s, 1H), 8.77(s, 2H). MS SEI m/zrelative intensity:M+H, 511.2(100).

Example 141

[0420] This example illustrates the levels of activity associated withrepresentative compounds of the invention. TABLE 1

R′ R″ R′″ IC50 B. su S. au E. c(tolC) 3-CF₃ 4-Cl 3-Cl +++ +++ +++ +++3-CF₃ 4-F H ++ ++ + +++ 3-NO₂ 4-Cl H ++ + + + 3-CF₃ 4-Cl H +++ ++ ++++++ 3-OCF₃ H 3-Cl ++ +++ ++ +++ 3-Cl 4-Cl 3-F ++ ++ ++ +++ 3-CF₃ H 3-F++ ++ ++ +++ 3-CF₃ H 3-Br ++ +++ ++ +++ 3-CF₃ H 3-CN + + + ++ 3-CF₃ H3-OPh + +++ +++ +++ 4-Cl H 3-Cl + ++ ++ +++ 3-CF₃ 5-CF₃ H + ++ ++ +++

Example 141

[0421] This example illustrates the levels of RNA polymerase inhibitoryand antibacterial activity associate with representative compounds ofthe invention. TABLE 2 RNA-pol RNA-pol IC₅₀ (μM) MIC (μM) IC₅₀ (μM) MIC(μM) Compound S. aureus S. aureus E. coli E. coli (tolC) 109 + +++ +++++ 110 + ++ + + 111 + ++ +++ 112 + + ++ +++ 113 +++ ++ +++ 114 + ++++++ +++ 115 + +++ + +++ 116 + +++ +++ +++ 117 +++ +++ + 118 + +++ +++119 +++ +++ 120 ++ +++ + +++ 121 + +++ + 122 ++ +++ + 123 +++ +++ + 124++ +++ + 125 ++ +++ +++ 126 +++ + +++ 127 ++ + + 128 + +++ +++ 129 ++++ + 130 + +++ + 131 +++ +++ + 132 ++ +++ +++ 133 ++ +++ +++ 134 ++++++ + 135 ++ +++ + 136 +++ +++ + 137 ++ +++ +++ 138 ++ +++ +++ 139 +++++ +++ 140 +++ +

[0422] All publications and patent applications cited in thisspecification are herein icorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample.

What is claimed is:
 1. A compound having the formula: A-X-M-Y-B or apharmaceutically acceptable salt thereof, wherein A and B are eachmembers independently selected from the group consisting of substitutedand unsubstituted aryl and substituted and unsubstituted heteroaryl; Xand Y are each members independently selected from the group consistingof: a bond

with the proviso that at least one of X or Y is a bond, and wherein thesubscript m is 0, 1 or 2; the subscript n is 1 or 2; W is a memberselected from the group consisting of O, N—OR⁵, N—NR¹R², N—NR¹C(O)R⁶ andN—OC(O)R⁶; R¹, R², R³, and R⁵ are each members independently selectedfrom the group consisting of H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl; R⁴ is a member selected from thegroup consisting of H, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)acylamino, and(C₁-C₈)heteroalkyl; and R⁶ is a member selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino and (C₁-C₈)heteroalkyl; and M is a divalent linkinggroup selected from the group consisting of:

wherein U is a member selected from the group consisting of:

R⁷ and R⁸ are each independently members selected from the groupconsisting of H, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino and di(C₁-C₆)alkylamino; R⁹ is a member selected fromthe group consisting of H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl; R¹⁰ is a member selected from thegroup consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl andheteroaryl(C₁-C₆)alkyl; and R¹¹ and R¹² are members independentlyselected from the group consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, C(O)R¹⁴, C(O)OR¹⁴, C(O)—NR¹⁴R¹⁵, S(O)₂R¹³ andS(O)₂NR¹⁴R¹⁵; wherein R¹³ is a member selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)heteroalkyl, phenyl and substituted phenyl; andR¹⁴ and R¹⁵ are each members independently selected from the groupconsisting of H, (C₁-C₆)alkyl and (C₁-C₆)heteroalkyl.
 2. A compound ofclaim 1, wherein X and Y are independently selected from the groupconsisting of: a bond


3. A compound of claim 1, wherein X and Y are each independentlyselected from the group consisting of: a bond


4. A compound of claim 1, wherein X and Y are each independentlyselected from the group consisting of: a bond


5. A compound of claim 1, wherein M is


6. A compound of claim 1, wherein X and Y are each a bond, and M is

wherein U is selected from the group consisting of


7. A compound of claim 6, wherein U is selected from the groupconsisting of


8. A compound of claim 1, said compound having the formula:


9. A compound of claim 8, wherein A is a phenyl group substituted withfrom one to three substituents selected from the group consisting of(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy,halogen, nitro, phenyl, naphthyl, pyrrolyl, pyrazolyl and —NR¹⁶R¹⁷wherein R¹⁶ and R¹⁷ are independently selected from the group consistingof hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl or are combined withthe nitrogen atom to which each is attached to form a four-, five-, six-or seven-membered ring optionally having additional heteroatoms as ringmembers and optionally having additional substituents selected from thegroup consisting of (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and phenyl.
 10. Acompound of claim 8, wherein B is a phenyl group substituted with fromone to three substituents selected from the group consisting of(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, phenyl and phenoxy.
 11. A compound of claim8, wherein A is a phenyl group substituted with from one to threesubstituents selected from the group consisting of (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen and —NR¹⁶R¹⁷wherein R¹⁶ and R¹⁷ are independently selected from the group consistingof hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl or are combined withthe nitrogen atom to which each is attached to form a four-, five-, six-or seven-membered ring optionally having additional heteroatoms as ringmembers and optionally having additional substituents selected from thegroup consisting of (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and phenyl, and Bis a phenyl group substituted with from one to three substituentsselected from the group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy halogen, phenyland phenoxy.
 12. A compound of claim 8, wherein A is selected from thegroup consisting of substituted or unsubstituted thienyl, substituted orunsubstituted furanyl, substituted or unsubstituted indolyl, substitutedor unsubstituted benzothienyl, substituted or unsubstitutedbenzothienyl, and radicals of the formulae:

wherein R¹⁸ is a member selected from the group consisting of(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy and halogen.
 13. A compound of claim 8, wherein A isselected from the group consisting of substituted or unsubstitutedbenzofuranyl, substituted or unsubstituted benzothienyl, substituted orunsubstituted indolyl, substituted or unsubstituted benzimidazolyl,substituted or unsubstituted benzthiazolyl and substituted orunsubstituted benzoxazolyl.
 14. A method of reducing bacterial growth ona surface, said method comprising contacting said surface with acompound of claim
 1. 15. A method of treating a bacterial infectioncomprising contacting a subject in need of such treatment with aneffective amount of a compound having the formula: A-X-M-Y-B or apharmaceutically acceptable salt thereof, wherein A and B are eachmembers independently selected from the group consisting of substitutedand unsubstituted aryl and substituted and unsubstituted heteroaryl; Xand Y are each members independently selected from the group consistingof: a bond

with the proviso that at least one of X or Y is a bond, and wherein thesubscript m is 0, 1 or 2; the subscript n is 1 or 2; W is a memberselected from the group consisting of O, N—OR⁵, N—NR¹R², N—NR¹C(O)R⁶ andN—OC(O)R⁶; R¹, R², R³ and R⁵ are each members independently selectedfrom the group consisting of H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl; R⁴ is a member selected from thegroup consisting of H, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,(C₁-C₆)allylamino, di(C₁-C₆)alkylamino, (C₁-C₆)acylamino, and(C₁-C₈)heteroalkyl; and R⁶ is a member selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino and (C₁-C₈)heteroalkyl; and M is a divalent linkinggroup selected from the group consisting of:

wherein U is a member selected from the group consisting of:

R⁷ and R⁸ are each members independently selected from the groupconsisting of H, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino and di(C₁-C₆)alkylamino; R⁹ is a member selected fromthe group consisting of H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl; R¹⁰ is a member selected from thegroup consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl andheteroaryl(C₁-C₆)alkyl; and R¹¹ and R¹² are members independentlyselected from the group consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, C(O)R¹⁴, C(O)OR¹⁴, C(O)—NR¹⁴R¹⁵, S(O)₂R¹³ andS(O)₂NR¹⁴R¹⁵; wherein R¹³ is a member selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)heteroalkyl, phenyl and substituted phenyl; andR¹⁴ and R¹⁵ are each members independently selected from the groupconsisting of H, (C₁-C₆)alkyl and (C₁-C₆)heteroalkyl.
 16. A method inaccordance with claim 15, wherein X and Y are independently selectedfrom the group consisting of: a bond


17. A method in accordance with claim 15, wherein X and Y are eachindependently selected from the group consisting of: a bond


18. A method in accordance with claim 15, wherein X and Y are each abond, and M is

wherein U is selected from the group consisting of


19. A method in accordance with claim 15, said compound having theformula:


20. A method in accordance with claim 19, wherein A is a phenyl groupsubstituted with from one to three substituents selected from the groupconsisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, nitro, phenyl, naphthyl, pyrrolyl, pyrazolyland —NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ are independently selected from thegroup consisting of hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl or arecombined with the nitrogen atom to which each is attached to form afour-, five-, six- or seven-membered ring optionally having additionalheteroatoms as ring members and optionally having additionalsubstituents selected from the group consisting of (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl and phenyl.
 21. A method in accordance with claim 19,wherein B is a phenyl group substituted with from one to threesubstituents selected from the group consisting of (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy,halogen, phenyl and phenoxy.
 22. A method in accordance with claim 19,wherein A is a phenyl group substituted with from one to threesubstituents selected from the group consisting of (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen and —NR¹⁶R¹⁷wherein R¹⁶ and R¹⁷ are independently selected from the group consistingof hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl or are combined withthe nitrogen atom to which each is attached to form a four-, five-, six-or seven-membered ring optionally having additional heteroatoms as ringmembers and optionally having additional substituents selected from thegroup consisting of (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and phenyl, and Bis a phenyl group substituted with from one to three substituentsselected from the group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen, phenyland phenoxy.
 23. A method in accordance with claim 19, wherein A isselected from the group consisting of substituted or unsubstitutedthienyl, substituted or unsubstituted furanyl, substituted orunsubstituted indolyl, substituted or unsubstituted benzothienyl,substituted or unsubstituted benzothienyl, and radicals of the formulae:

wherein R¹⁸ is a member selected from the group consisting of(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy and halogen.
 24. A method in accordance with claim 23,wherein A is selected from the group consisting of substituted orunsubstituted benzofuranyl, substituted or unsubstituted benzothienyl,substituted or unsubstituted indolyl, substituted or unsubstitutedbenzimidazolyl, substituted or unsubstituted benzthiazolyl andsubstituted or unsubstituted benzoxazolyl.
 25. A composition comprisinga pharmaceutically acceptable excipient in admixture with a compoundhaving the formula: A-X-M-Y-B or a pharmaceutically acceptable saltthereof, wherein A and B are each members independently selected fromthe group consisting of substituted and unsubstituted aryl andsubstituted and unsubstituted heteroaryl; X and Y are each membersindependently selected from the group consisting of: a bond

with the proviso that at least one of X or Y is a bond, and wherein thesubscript m is 0, 1 or 2; the subscript n is 1 or 2; W is a memberselected from the group consisting of O, N—OR⁵, N—NR¹R², N—NR¹C(O)R⁶ andN—OC(O)R⁶; R¹, R², R³ and R⁵ are each members independently selectedfrom the group consisting of H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl; R⁴ is a member selected from thegroup consisting of H, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)acylamino, and(C₁-C₈)heteroalkyl; and R⁶ is a member selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino and (C₁-C₈)heteroalkyl; and M is a divalent linkinggroup selected from the group consisting of:

wherein U is a member selected from the group consisting of:

R⁷ and R⁸ are each members independently selected from the groupconsisting of H, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino and di(C₁-C₆)alkylamino; R⁹ is a member selected fromthe group consisting of H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,heteroaryl and heteroaryl(C₁-C₆)alkyl; R¹⁰ is a member selected from thegroup consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl andheteroaryl(C₁-C₆)alkyl; and R¹¹ and R¹² are members independentlyselected from the group consisting of H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, C(O)R¹⁴, C(O)OR¹⁴, C(O)—NR¹⁴R¹⁵, S(O)₂R¹³ andS(O)₂NR¹⁴R¹⁵; wherein R¹³ is a member selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)heteroalkyl, phenyl and substituted phenyl; andR¹⁴ and R¹⁵ are each members independently selected from the groupconsisting of H, (C₁-C₆)alkyl and (C₁-C₆)heteroalkyl.
 26. A compositionin accordance with claim 25, wherein X and Y are independently selectedfrom the group consisting of: a bond


27. A composition in accordance with claim 25, wherein X and Y are eachindependently selected from the group consisting of: a bond


28. A composition in accordance with claim 25, wherein X and Y are eacha bond, and M is

wherein U is selected from the group consisting of


29. A composition in accordance with claim 25, said compound having theformula:


30. A composition in accordance with claim 29, wherein A is a phenylgroup substituted with from one to three substituents selected from thegroup consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, nitro, phenyl, naphthyl, pyrrolyl, pyrazolyland —NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ are independently selected from thegroup consisting of hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl or arecombined with the nitrogen atom to which each is attached to form afour-, five-, six- or seven-membered ring optionally having additionalheteroatoms as ring members and optionally having additionalsubstituents selected from the group consisting of (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl and phenyl.
 31. A composition in accordance withclaim 29, wherein B is a phenyl group substituted with from one to threesubstituents selected from the group consisting of (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxyhalogen, phenyl and phenoxy.
 32. A composition in accordance with claim29, wherein A is a phenyl group substituted with from one to threesubstituents selected from the group consisting of (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen and —NR¹⁶R¹⁷wherein R¹⁶ and R¹⁷ are independently selected from the group consistingof hydrogen, (C₁-C₈)alkyl and (C₁-C₈)heteroalkyl or are combined withthe nitrogen atom to which each is attached to form a four-, five-, six-or seven-membered ring optionally having additional heteroatoms as ringmembers and optionally having additional substituents selected from thegroup consisting of (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and phenyl, and Bis a phenyl group substituted with from one to three substituentsselected from the group consisting of (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen, phenyland phenoxy.
 33. A composition in accordance with claim 29, wherein A isselected from the group consisting of substituted or unsubstitutedthienyl, substituted or unsubstituted furanyl, substituted orunsubstituted indolyl, substituted or unsubstituted benzothienyl,substituted or unsubstituted benzothienyl, and radicals of the formulae:

wherein R¹⁸ is a member selected from the group consisting of(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)heteroalkyl, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy and halogen.
 34. A composition in accordance withclaim 33, wherein A is selected from the group consisting of substitutedor unsubstituted benzofuranyl, substituted or unsubstitutedbenzothienyl, substituted or unsubstituted indolyl, substituted orunsubstituted benzimidazolyl, substituted or unsubstituted benzthiazolyland substituted or unsubstituted benzoxazolyl.